Effects of a high-fat diet on memory & cognition
Neurogenesis — the creation of new brain cells — occurs of course at a great rate in the very young. For a long time, it was not thought to occur in adult brains — once you were grown, it was thought, all you could do was watch your brain cells die!
Adult neurogenesis (the creation of new brain cells in adult brains) was first discovered in 1965, but only recently has it been accepted as a general phenomenon that occurs in many species, including humans (1998).
It's now widely accepted that adult neurogenesis occurs in the subgranular zone of the dentate gyrus within the hippocampus and the subventricular zone (SVZ) lining the walls of the lateral ventricles within the forebrain. It occurs, indeed, at a quite frantic rate — some 9000 new cells are born in the dentate gyrus every day in young adult rat brains — but under normal circumstances, at least half of those new cells will die within one or two months.
The neurons produced in the SVZ are sent to the olfactory bulb, while those produced in the dentate gyrus are intended for the hippocampus.
Adult neurogenesis might occur in other regions, but this is not yet well-established. However, recent research has found that small, non-pyramidal, inhibitory interneurons are being created in the cortex and striatum. These new interneurons appear to arise from a previously unknown class of local precursor cells. These interneurons make and secrete GABA (see below for why GABA is important), and are thought to play a role in regulating larger types of neurons that make long-distance connections between brain regions.
New neurons are spawned from the division of neural precursor cells — cells that have the potential to become neurons or support cells. How do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)?
Observation that neuroblasts traveled to the olfactory bulb from the SVZ through tubes formed by astrocytes has led to an interest in the role of those support cells. It's now been found that astrocytes encourage both precursor cell proliferation and their maturation into neurons — precursor cells grown on glia divide about twice as fast as they do when grown on fibroblasts, and are about six times more likely to become neurons.
Adult astrocytes are only about half as effective as embryonic astrocytes in promoting neurogenesis.
It’s been suggested that the role of astrocytes may help explain why neurogenesis only occurs in certain parts of the brain — it may be that there’s something missing from the glial cells in those regions.
The latest research suggests that the astrocytes influence the decision through a protein that it secretes called Wnt3. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased.
How are these new neurons then integrated into existing networks? Mouse experiments have found that the brain chemical called GABA is critical. Normally, GABA inhibits neuronal signals, but it turns out that with new neurons, GABA has a different effect: it excites them, and prepares them for integration into the adult brain. Thus a constant flood of GABA is needed initially; the flood then shifts to a more targeted pulse that gives the new neuron specific connections that communicate using GABA; finally, the neuron receives connections that communicate via another chemical, glutamate. The neuron is now ready to function as an adult neuron, and will respond to glutamate and GABA as it should.
The creation and development of new neurons in the adult brain is very much a "hot" topic right now — it's still very much a work-in-progress. However, it is clear that other brain chemicals are also involved. An important one is BDNF (brain-derived neurotrophic factor), which seems to be needed during the proliferation of hippocampal precursor cells to trigger their transformation into neurons.
Other growth factors have been found to stimulate proliferation of hippocampal progenitor cells: FGF-2 (fibroblast growth factor-2) and EGF (epidermal growth factor).
Recently it has been discovered that the normal form of the prion protein which, when malformed, causes mad cow disease, is also involved in neurogenesis. These proteins, in their normal form, are found throughout our bodies, and particularly in our brains. Now it seems that the more of these prion proteins that are available, the faster neural precursor cells turn into neurons.
The immune system's T cells (which recognize brain proteins) are also critically involved in enabling neurogenesis to occur. Among mice given environmental enrichment, only those with healthy T-cells had their production of new neurons boosted.
A number of factors have been found to affect the creation and survival of new neurons. For a start, damage to the brain (from a variety of causes) can provoke neurogenesis.
Moderate alcohol consumption over a relatively long period of time can also enhance the formation of new nerve cells in the adult brain (this may be related to alcohol's enhancement of GABA's function). Excess alcohol, however, has a detrimental effect on the formation of new neurons in the adult hippocampus. But although neurogenesis is inhibited during alcohol dependency, it does recover. A pronounced increase in new neuron formation in the hippocampus was found within four-to-five weeks of abstinence. This included a twofold burst in brain cell proliferation at day seven of abstinence.
Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis, but a new study suggests that cannabinoids also promote neurogenesis. The study involved a synthetic cannabinoid, which increased the proliferation of progenitor cells in the hippocampal dentate gyrus of mice, in a similar manner as some antidepressants have been shown to do. The cannabinoid also produced similar antidepressant effects. Further research is needed to confirm this early finding.
If antidepressants promote neurogenesis, it won't be surprising to find that chronic stress, anxiety and depression are associated with losing hippocampal neurons. A rat study has also found that stress in early life can permanently impair neurogenesis in the hippocampus.
Showing the other side of this picture, perhaps, an intriguing rat study found that status affected neurogenesis in the hippocampus, with high-status animals having around 30% more neurons in their hippocampus after being placed in a naturalistic setting with other rats.
Also, a study into the brains of songbirds found that birds living in large groups have more new neurons and probably a better memory than those living alone.
Both physical activity and environmental enrichment (“mental stimulation”) have been shown to affect both how many cells are born in the dentate gyrus of rats and how many survive. Learning that uses the hippocampus has also been shown to have a positive effect, although results here have been inconsistent.
Inconsistent results from studies looking at neurogenesis are, it is suggested, largely because of a confusion between proliferation and survival. Neurogenesis is measured in terms of these two factors, which researchers often fail to distinguish between: the generation of new brain cells, and their survival. But these are separate factors, that are independently affected by various factors.
The inconsistency found in the effects of learning may also be partly explained by the complex nature of the effects. For example, during the later phase of learning, when performance is starting to plateau, neurons created during the late phase were more likely to survive, but neurons created during the early phase of more rapid learning disappeared. It’s speculated that that this may be a “pruning” process by which cells that haven’t made synaptic connections are removed from the network.
And finally, rodent studies suggest a calorie-restricted diet may also be of benefit.
A few years ago, we were surprised by news that new neurons could be created in the adult brain. However, it’s remained a tenet that adult neurons don’t grow — this because researchers have found no sign that any structural remodelling takes place in an adult brain. Now a mouse study using new techniques has revealed that dramatic restructuring occurs in the less-known, less-accessible inhibitory interneurons. Dendrites (the branched projections of a nerve cell that conducts electrical stimulation to the cell body) show sometimes dramatic growth, and this growth is tied to use, supporting the idea that the more we use our minds, the better they will be.
For more, see the research reports
A pilot study involving 106 participants of the Rush Memory and Aging Project who had experienced a stroke followed participants for an average of 5.9 years, testing their cognitive function and monitoring their eating habits using food journals. It was found that those whose diets scored highest on the MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay) diet score had substantially slower rates of cognitive decline than those who scored lowest. The estimated effect of the diet remained strong even after taking into account participants' level of education and participation in cognitive and physical activities. Those who instead scored high on the Mediterranean or DASH diets did not show the same slower decline.
Both the Mediterranean and DASH diets have been shown to be protective against coronary artery disease and stroke, but this finding suggests the MIND diet is better for overall brain health.
The MIND diet is a hybrid of the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets. It has 15 components: 10 “brain-healthy food groups” and five unhealthy groups (red meat, butter, cheese, pastries and sweets, and fried or fast food).
To adhere to the MIND diet, you need to
The researchers stress that this is a preliminary study, observational only. They are currently seeking participants for a wider, intervention study.
Laurel J. Cherian & Martha Clare Morris: Presentation at the American Stroke Association's International Stroke Conference 2018 in Los Angeles, January 25.
A mouse study suggests that resveratrol—a compound abundant in red wine—may moderate some of a high-fat diet’s negative effects on the immune system.
A large long-running study has found that eating a diet rich in animal proteins during middle age makes you four times more likely to die of cancer than a low-protein diet (a mortality risk factor comparable to smoking), 74% more likely to die of any cause within the 20-year study period, and five times more likely to die of diabetes.
A study involving 61 women, of whom 33 were chronically stressed caring for a spouse or parent with dementia, has found that highly stressed people who ate a lot of high-fat, high-sugar food were likely to have:
This association was not found among the low-stress women who ate the same amount of unhealthy food.
The findings are consistent with animal studies.
A 2-year trial involving 59 patients with type 2 diabetes has found that those on a low-carbohydrate diet showed lower levels of inflammation compared with those on a traditional low-fat diet. Weight loss was similar in both groups.
A large study reveals that a diet with high levels of carbohydrate and sugar greatly increases the chance of developing MCI or dementia, while high levels of fat and protein reduce the risk.
In a large Mayo Clinic study, self-reported diet was found to be significantly associated with the risk of seniors developing mild cognitive impairment or dementia over a four-year period.
The study involved 1,230 older adults (70-89) who completed a 128-item food-frequency questionnaire about their diet during the previous year. Of these, around three-quarters (937) showed no signs of cognitive impairment at the beginning of the study period, and were asked to return for follow-up cognitive assessments. These assessments took place every 15 months. After about four years, 200 (21%) had developed mild cognitive impairment (MCI) or dementia.
The likelihood of cognitive deterioration was significantly affected by the type of diet. Those with the highest carbohydrate intake were nearly twice as likely to develop cognitive impairment compared to those with the lowest carbohydrate consumption, and when total fat and protein intake were taken into account, they were 3.6 times likelier to develop impairment.
Those with the highest sugar intake were 1.5 times more likely to develop cognitive impairment.
But — a finding that will no doubt surprise many — those with the highest fat consumption were 42% less likely to develop cognitive impairment, compared to those with the lowest level of fats.
Less surprisingly, those with highest intake of protein had a reduced risk of 21%.
In other words, the worst diet you can have, if you want to keep your brain healthy, is one that receives most of its calories from carbohydrates and sugar, and relatively little from fats and protein.
The findings about carbs, sugar, and protein are consistent with other research. The finding regarding fats is somewhat more surprising. The inconsistency may lie in the type of fat. Research implicating high-fat diets as a risk factor in Alzheimer’s have used saturated fats. Diets high in olive oil, on the other hand, have been found to be beneficial.
It seems likely that the danger of carbs and too much sugar lies in the effects on glucose and insulin metabolism. Saturated fats also interfere with glucose metabolism. Alzheimer’s has sometimes been called Type 3 diabetes, because of its association with insulin problems.
Roberts RO, Roberts LA, Geda YE, Cha RH, Pankratz VS, O'Connor HM, Knopman DS, Petersen RC. 2012. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. Journal of Alzheimers Disease, 32(2), 329-39.
A mouse study provides more support for the value of exercise in preventing Alzheimer’s disease, and shows one of the ways in which it does so.
A study designed to compare the relative benefits of exercise and diet control on Alzheimer’s pathology and cognitive performance has revealed that while both are beneficial, exercise is of greater benefit in reducing Alzheimer’s pathology and cognitive impairment.
The study involved mice genetically engineered with a mutation in the APP gene (a familial risk factor for Alzheimer’s), who were given either a standard diet or a high-fat diet (60% fat, 20% carbohydrate, 20% protein vs 10% fat, 70% carbohydrate, 20% protein) for 20 weeks (from 2-3 to 7-8 months of age). Some of the mice on the high-fat diet spent the second half of that 20 weeks in an environmentally enriched cage (more than twice as large as the standard cage, and supplied with a running wheel and other objects). Others on the high-fat diet were put back on a standard diet in the second 10 weeks. Yet another group were put on a standard diet and given an enriched cage in the second 10 weeks.
Unsurprisingly, those on the high-fat diet gained significantly more weight than those on the standard diet, and exercise reduced that gain — but not as much as diet control (i.e., returning to a standard diet) did. Interestingly, this was not the result of changes in food intake, which either stayed the same or slightly increased.
More importantly, exercise and diet control were roughly equal in reversing glucose intolerance, but exercise was more effective than diet control in ameliorating cognitive impairment. Similarly, while amyloid-beta pathology was significantly reduced in both exercise and diet-control conditions, exercise produced the greater reduction in amyloid-beta deposits and level of amyloid-beta oligomers.
It seems that diet control improves metabolic disorders induced by a high-fat diet — conditions such as obesity, hyperinsulinemia and hypercholesterolemia — which affects the production of amyloid-beta. However exercise is more effective in tackling brain pathology directly implicated in dementia and cognitive decline, because it strengthens the activity of an enzyme that decreases the level of amyloid-beta.
Interestingly, and somewhat surprisingly, the combination of exercise and diet control did not have a significantly better effect than exercise alone.
The finding adds to the growing pile of evidence for the value of exercise in maintaining a healthy brain in later life, and helps explain why. Of course, as I’ve discussed on several occasions, we already know other mechanisms by which exercise improves cognition, such as boosting neurogenesis.
 Maesako, M., Uemura K., Kubota M., Kuzuya A., Sasaki K., Hayashida N., et al.
(2012). Exercise Is More Effective than Diet Control in Preventing High Fat Diet-induced β-Amyloid Deposition and Memory Deficit in Amyloid Precursor Protein Transgenic Mice.
Journal of Biological Chemistry. 287(27), 23024 - 23033.
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