The nutritional and clinical significance of lipid rafts

Purpose of review Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Recent findings In-vitro and ex-vivo studies suggest that dietary n-3 polyunsaturated fatty acids (PUFAs) may exert immunosuppressive and anticancer effects through changes in lipid raft organization. In addition, gangliosides and cholesterol may modulate lipid raft organization in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth. The roles of fatty acids and gangliosides, especially in relation to lipid rafts, in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer’s disease are poorly understood and require further investigation. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are starting to emerge, and indicate compelling evidence for the growing importance of membrane microdomains in health and disease. Summary In-vitro and animal studies show that n-3 PUFAs, cholesterol, and gangliosides modulate the structure and composition of lipid rafts, potentially influencing a wide range of biological processes, including immune function, neuronal signaling, cancer cell growth, entry of pathogens through the gut barrier, and insulin resistance in metabolic disorders. The physiological, clinical, and nutritional relevance of these observations remains to be determined.

Aging is associated with positive responding to neutral information but reduced recovery from negative information

Studies on aging and emotion suggest an increase in reported positive affect, a processing bias of positive over negative information, as well as increasingly adaptive regulation in response to negative events with advancing age. These findings imply that older individuals evaluate information differently, resulting in lowered reactivity to, and/or faster recovery from, negative information, while maintaining more positive responding to positive information. We examined this hypothesis in an ongoing study on Midlife in the US (MIDUS II) where emotional reactivity and recovery were assessed in a large number of respondents (N = 159) from a wide age range (36–84 years). We recorded eye-blink startle magnitudes and corrugator activity during and after the presentation of positive, neutral and negative pictures. The most robust age effect was found in response to neutral stimuli, where increasing age is associated with a decreased corrugator and eyeblink startle response to neutral stimuli. These data suggest that an age-related positivity effect does not essentially alter the response to emotion-laden information, but is reflected in a more positive interpretation of affectively ambiguous information. Furthermore, older women showed reduced corrugator recovery from negative pictures relative to the younger women and men, suggesting that an age-related prioritization of well-being is not necessarily reflected in adaptive regulation of negative affect.

Current intakes of EPA and DHA in European populations and the potential of animal-derived foods to increase them

The beneficial effects of long-chain (C chain >= 20) n-3 PUFA are well documented and, overall, increased intake reduces risk of CVD. Recent evidence also points to a role in reducing, age-related decline in cognitive function. The two key fatty acids are EPA (20:5) and DHA (22:6), with current UK recommendation for adults being 450 mg EPA + DHA/d. Whilst some EPA and DHA can be synthesised in vivo from alpha-linolenic acid, recent data indicate this source to be very limited, Suggesting that EPA and DHA should be classified as dietary essentials. In many parts of Europe the daily intake of EPA + DHA by adults and especially young adults (18-24 years) is < 100 mg/d, since many never eat oily fish. Poultry meat contributes small but worthwhile amounts of EPA+DHA. Studies to enrich the EPA+DHA content of animal-derived foods mainly use fish oil in the diet of the animal. Recent work has shown that such enrichment has the potential to provide to the UK adult diet a daily intake of EPA+DHA of about 230 mg, with poultry meat providing the largest amount (74 mg). There are. however. concerns that the Continued and possibly increased use of fish oils in animals diets is not Sustainable and alternative approaches are being examined, including the genetic modification of certain plants to allow them to synthesise EPA and DHA from shorter-chain precursors.

Current intakes of EPA and DHA in European populations and the potential of animal-derived foods to increase them

The beneficial effects of long-chain (C chain >= 20) n-3 PUFA are well documented and, overall, increased intake reduces risk of CVD. Recent evidence also points to a role in reducing, age-related decline in cognitive function. The two key fatty acids are EPA (20:5) and DHA (22:6), with current UK recommendation for adults being 450 mg EPA + DHA/d. Whilst some EPA and DHA can be synthesised in vivo from alpha-linolenic acid, recent data indicate this source to be very limited, Suggesting that EPA and DHA should be classified as dietary essentials. In many parts of Europe the daily intake of EPA + DHA by adults and especially young adults (18-24 years) is < 100 mg/d, since many never eat oily fish. Poultry meat contributes small but worthwhile amounts of EPA+DHA. Studies to enrich the EPA+DHA content of animal-derived foods mainly use fish oil in the diet of the animal. Recent work has shown that such enrichment has the potential to provide to the UK adult diet a daily intake of EPA+DHA of about 230 mg, with poultry meat providing the largest amount (74 mg). There are. however. concerns that the Continued and possibly increased use of fish oils in animals diets is not Sustainable and alternative approaches are being examined, including the genetic modification of certain plants to allow them to synthesise EPA and DHA from shorter-chain precursors.

Effect of time of day and rabbit strain on patterns of aortic wall permeability

Lipid deposits occur more frequently downstream of branch points than upstream in immature rabbit and human aortas but the opposite pattern is seen in mature vessels. These distributions correlate spatially with age-related patterns of aortic permeability, observed in rabbits, and may be determined by them. The mature but not the immature pattern of permeability is dependent on endogenous nitric oxide synthesis. Although the transport patterns have hitherto seemed robust, recent studies have given the upstream pattern in some mature rabbits but the downstream pattern in others. Here we show that transport in mature rabbits is significantly skewed to the downstream pattern in the afternoon compared with the morning (P < 0.05), and switches from a downstream to an upstream pattern at around 21 months in rabbits of the Murex strain, but at twice this age in Highgate rabbits (P < 0.001). The effect of time of day was not explained by changes in nitric oxide production, assessed from plasma levels of nitrate and nitrate, nor did it correlate with conduit artery tone, assessed from the shape of the peripheral pulse wave. The effect of strain could not be explained by variation in nitric oxide production nor by differences in wall structure. The effects of time of day and rabbit strain on permeability patterns explain recent discrepancies, provide a useful tool for investigating underlying mechanisms and may have implications for human disease.

The Nutritional Significance of Lipid Rafts

The structure, size, stability, and functionality of lipid rafts are still in debate, but recent techniques allowing direct visualization have characterized them in a wide range of cell types. Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. However, it is not clear whether dietary polyunsaturated fatty acids (PUFAs) are incorporated into raft lipids or whether their low affinity to cholesterol disallows this and causes phase separation from rafts and displacement of raft proteins. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Although there is increasing evidence to suggest that membrane microdomains, and their modulation, have an impact in health and disease, it is too early to judge whether modulation of lipid rafts is responsible for the immunomodulatory effects of n-3 PUFA. In addition to dietary fatty acids, gangliosides and cholesterol may also modulate microdomains in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth by n-3 PUFA. The roles of fatty acids and gangliosides in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require clarification, particularly with respect to the contribution of lipid rafts. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are only just emerging, but compelling evidence indicates the growing importance of membrane microdomains in health and disease.

Flavonoids and cognition: The molecular mechanisms underlying their behavioural effects

Evidence Suggests that a group of phytochemicals known as flavonoids are highly effective in reversing age-related declines in neuro-cognitive performance through their ability to interact with the cellular and molecular architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative Processes. In particular, they may increase the number of, and strength of, connections between neurons, via their specific interactions with the ERK and Akt signalling pathways, leading to an increase in neurotrophins Such as BDNF. Concurrently, their effects on the peripheral and Cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to reduce neuronal damage and losses induced by various neurotoxic species and neuroinflammation. Together, these processes act to maintain the number and quality of synaptic connections in the brain. a factor known to be essential for efficient LTP, synaptic plasticity and ultimately the efficient working of memory. (C) 2009 Elsevier Inc. All rights reserved.

The impact of flavonoids on memory: physiological and molecular considerations

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory acquisition, consolidation, storage and retrieval. These low molecular weight polyphenols are widespread in the human diet, are absorbed to only a limited degree and localise in the brain at low concentration. However, they have been found to be highly effective in reversing age-related declines in memory via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. These interactions include an ability to activate signalling pathways, critical in controlling synaptic plasticity, and a potential to induce vascular effects capable of causing new nerve cell growth in the hippocampus. Their ability to activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor responsible for increasing the expression of a number of neurotrophins important in de. ning memory, will be discussed. How these effects lead to improvements in memory through induction of synapse growth and connectivity, increases in dendritic spine density and the functional integration of old and new neurons will be illustrated. The overall goal of this critical review is to emphasize future areas of investigation as well as to highlight these dietary agents as promising candidates for the design of memory-enhancing drugs with relevance to normal and pathological brain ageing (161 references).

The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.

Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels

Phytochemical-rich foods have been shown to be effective at reversing age-related deficits in memory in both animals and humans. We show that a supplementation with a blueberry diet (2% w/w) for 12 weeks improves the performance of aged animals in spatial working memory tasks. This improvement emerged within 3 weeks and persisted for the remainder of the testing period. Memory performance correlated well with the activation of cAMP-response element-binding protein (CREB) and increases in both pro- and mature levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. Changes in CREB and BDNF in aged and blueberry-supplemented animals were accompanied by increases in the phosphorylation state of extracellular signal-related kinase (ERK1/2), rather than that of calcium calmodulin kinase (CaMKII and CaMKIV) or protein kinase A. Furthermore, age and blueberry supplementation were linked to changes in the activation state of Akt, mTOR, and the levels of Arc/Arg3.1 in the hippocampus, suggesting that pathways involved in de novo protein synthesis may be involved. Although causal relationships cannot be made among supplementation, behavior, and biochemical parameters, the measurement of anthocyanins and flavanols in the brain following blueberry supplementation may indicate that changes in spatial working memory in aged animals are linked to the effects of flavonoids on the ERK-CREB-BDNF pathway. (c) 2008 Elsevier Inc. All Fights reserved.

False recognition of abstract versus common objects in older and younger adults: testing the semantic categorization account

Older adults often demonstrate higher levels of false recognition than do younger adults. However, in experiments using novel shapes without preexisting semantic representations, this age-related elevation in false recognition was found to be greatly attenuated. Two experiments tested a semantic categorization account of these findings, examining whether older adults show especially heightened false recognition if the stimuli have preexisting semantic representations, such that semantic category information attenuates or truncates the encoding or retrieval of item-specific perceptual information. In Experiment 1, ambiguous shapes were presented with or without disambiguating semantic labels. Older adults showed higher false recognition when labels were present but not when labels were never presented. In Experiment 2, older adults showed higher false recognition for concrete but not abstract objects. The semantic categorization account was supported.

Endocannabinoid receptor antagonists: potential for obesity treatment

Obesity has been described as a global epidemic. Its increasing prevalence is matched by growing costs, not only to the health of the individual, but also to the medical services required to treat a range of obesity-related diseases. In most instances, obesity is a product of progressively less energetic lifestyles and the over-consumption of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. An important part of the process of developing new pharmacologic treatments for obesity lies in improving our understanding of the psychologic and physiologic processes that govern appetite and bodyweight regulation. Recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. Current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. Additionally, endocannabinoids appear to modulate central and peripheral processes associated with fat and glucose metabolism. Selective cannabinoid receptor antagonists have been shown to suppress the motivation to eat, and preferentially reduce the consumption of palatable, energy-dense foods. Additionally, these agents act to reduce adiposity through metabolic mechanisms that are independent of changes in food intake. Given the current state of evidence, we conclude that the endocannabinoids represent an exciting target for new anti-obesity therapies.

Diet, ageing and genetic factors in the pathogenesis of diverticular disease

Diverticular disease (DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK. This high prevalence ranks it as one of the most common bowel disorders in western nations. The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum. Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality. In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressureinduced damage to the colon wall amongst those with a low intake of dietary fiber. In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development. We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal. We have also identified several gaps in the knowledge base which need to be filled before we can complete

Understanding of auditory discourse in older adults: the effects of syntax and working memory

Background: As people age, language-processing ability changes. While several factors modify discourse comprehension ability in older adults, syntactic complexity of auditory discourse has received scant attention. This is despite the widely researched domain of syntactic processing of single sentences in older adults. Aims: The aims of this study were to investigate the ability of healthy older adults to understand stories that differed in syntactic complexity, and its relation to working memory. Methods & Procedures: A total of 51 healthy adults (divided into three age groups) took part. They listened to brief stories (syntactically simple and syntactically complex) and had to respond to false/true comprehension probes following each story. Working memory capacity (digit span, forward and backward) was also measured. Outcomes & Results: Differences were found in the ability of healthy older adults to understand simple and complex discourse. The complex discourse in particular was more sensitive in discerning age-related language patterns. Only the complex discourse task correlated moderately with age. There was no correlation between age and simple discourse. As far as working memory is concerned, moderate correlations were found between working memory and complex discourse. Education did not correlate with discourse, neither simple, nor complex. Conclusions: Older adults may be less efficient in forming syntactically complex representations and this may be influenced by limitations in working memory.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.