I have reported often on studies pointing to obesity as increasing your risk of developing dementia, and on the smaller evidence that calorie restriction may help fight age-related cognitive decline and dementia (and help you live longer). A new mouse study helps explain why eating less might help the brain.
It turns out that a molecule called CREB-1 is triggered by calorie restriction (defined as only 70% of normal consumption). cAMP Response Element Binding (CREB) protein is an essential component of long-term memory formation, and abnormalities in the expression of CREB have been reported in the brains of Alzheimer’s patients. Restoring CREB to Alzheimer’s mice has been shown to improve learning and memory impairment.
Animal models have also indicated a role for CREB in the improvements in learning and memory brought about by physical exercise. CREB seems to be vital for adult neurogenesis.
The current study found that, when CREB1 was missing (in mice genetically engineered to lack this molecule), calorie restriction had no cognitive benefits. CREB deficiency in turn drastically reduced the expression of Sirt-1. These proteins have been implicated in cardiac function, DNA repair and genomic stability (hence the connection to longevity). More recently, Sirt-1 has also been found to modulate synaptic plasticity and memory formation — an effect mediated by CREB. This role in regulating normal brain function appears to be quite separate from its cell survival functions.
The findings identify a target for drugs that could produce the same cognitive (and longevity) benefits without the need for such strict food reduction.
Reducing your eating and drinking to 70% of normal intake is a severe reduction. Recently, researchers at the National Institute on Ageing in Baltimore have suggested that the best way to cut calories to achieve cognitive benefits was to virtually fast (down to around 500 calories) for two days a week, while eating as much as you want on the other days. Their animal experiments indicate that timing is a crucial element if cognitive benefits are to accrue.
Another preliminary report, this time from the long-running Mayo Clinic study of aging, adds to the evidence that lower consumption reduces the risk of serious cognitive impairment. The first analysis of data has revealed that the risk of developing mild cognitive impairment more than doubled for those in the highest food consumption group (daily calorie consumption between 2,143 and 6,000) compared to those in the lowest (between 600 and 1,526 calories).
Calorie consumption was taken from food questionnaires in which respondents described their diets over the previous year, so must be taken with a grain of salt. Additionally, the analysis didn’t take into account types of food and beverages, or other lifestyle factors, such as exercise. Further analysis will investigate these matters in more depth.
The study involved 1,233 older adults, aged 70 to 89. Of these, 163 were found to have MCI.
None of this should be taken as a recommendation for severely restricting your diet. Certainly such behavior should not be undertaken without the approval of your doctor, but in any case, calorie restriction is only part of a much more complex issue concerning diet. I look forward to hearing more from the Mayo Clinic study regarding types of foods and interacting factors.
 Fusco, S., Ripoli C., Podda M V., Ranieri S C., Leone L., Toietta G., et al.
(2012). A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction.
Proceedings of the National Academy of Sciences. 109(2), 621 - 626.
The findings from the National Institute on Aging were presented at the annual meeting of the American Association for the Advancement of Science in Vancouver.
Geda, Y., Ragossnig, M., Roberts, L.K., Roberts, R., Pankratz, V., Christianson, T., Mielke, M., Boeve, B., Tangalos, E. & Petersen, R. 2012. Caloric Intake, Aging, and Mild Cognitive Impairment: A Population-Based Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.
Recent rat studies have indicated that significant calorie restriction lengthens lives, but the evidence for humans is rather more mixed. Now a German study of 50 healthy but overweight older adults (average age 60) has found that those who were on a balanced but severely restricted diet (reduced by 30%) for 3 months significantly improved their performance on a verbal memory test. Those who didn’t reduce their calorie intake but increased their consumption of unsaturated fatty acids (linked to improved cognition), and those who didn’t change their diets, showed little or no improvement. It’s important to note that the participants were overweight to start with; further research will be needed to see whether the same effect occurs with normal-weight older adults.
 Witte, A. V., Fobker M., Gellner R., Knecht S., & Floel A.
(2009). From the Cover: Caloric restriction improves memory in elderly humans.
Proceedings of the National Academy of Sciences. 106(4), 1255 - 1260.
A mouse study has found that beta-amyloid peptides can be reduced by restricting calorie intake, primarily through a low carbohydrate diet. Conversely, a high caloric intake based on saturated fat was shown to increase levels of beta-amyloid peptides. This is the first study to suggest that caloric restriction might inhibit the generation of beta-amyloid peptides, but there have been a number of studies providing evidence that high cholesterol, obesity, and other cardiovascular risk factors increase the likelihood of Alzheimer’s.
Qin, W. et al. 2006. Neuronal SIRT1 Activation as a Novel Mechanism Underlying the Prevention of Alzheimer Disease Amyloid Neuropathology by Calorie Restriction. Journal of Biological Chemistry, 281 (31), 21745-21754.
Restricting the diets of genetically engineered mice by 40% over 4 weeks reduced the build-up of plaques in the brain that are linked to Alzheimer's disease by 50%. It remains to be seen whether such dietary changes would similarly affect humans. Researchers are now looking to isolate the specific factors of the diet restriction which are important.
Patel, N.V., Gordon, M.N., Connor, K.E., Good, R.A., Engelman, R.W., Mason, J., Morgan, D.G., Morgan, T.E. & Finch, C.E. (in press). Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiology of Aging, In Press, Corrected Proof, Available online 25 November 2004.
A mouse study has found that although severe calorie restriction prevents certain aging-related changes in the brain, such as the accumulation of free radicals, and impairments in coordination and strength, the reduced diet did not seem to prevent age-related cognitive impairment.
Dugan, L.L. et al. 2004. Presented on Sunday, Oct. 24 at Neuroscience 2004, the Society for Neuroscience's 34th Annual Meeting in San Diego.
A new mouse study suggests fasting every other day may protect brain neurons as well as or better than either vigorous exercise or caloric restriction. The mice were allowed to eat as much as they wanted on non-fasting days, and did not, overall, eat fewer calories than the control group. Their nerve cells however, proved to be more resistant to neurotoxin injury or death than nerve cells of both the calorie-restricted mice or the control group. Previous research has found that meal-skipping diets can stimulate brain cells in mice to produce a protein called brain-derived neurotrophic factor (BDNF) that promotes the survival and growth of nerve cells. The researchers are now investigating the effects of meal-skipping on the cardiovascular system in laboratory rats.
A recent rat study has shown that certain proteins that increase with age and are linked to cell death were significantly reduced in the brains of rats whose calories were limited (but nutritionally dense, to guard against malnutrition). Moreover, the levels of a beneficial protein known to protect against neuron death were twice as high in older rats whose calories were restricted by 40%. This is consistent with a number of studies of other species that have found calorie restriction not only boosts life span and general health but also increases mental capacity.
 Shelke, R. R. J., & Leeuwenburgh C.
(2003). Life-long calorie restriction (CR) increases expression of apoptosis repressor with a caspase recruitment domain (ARC) in the brain.
FASEB J.. 02-0803fje - 02-0803fje.