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Alzheimer's Disease

Calories, SIRT1 and Alzheimer's

12 years, 1 month ago

1152  0
Posted on Sep 18, 2006, 7 a.m. By Bill Freeman

Calorie-restriction -- consuming 30-percent fewer calories than normal -- is the only scientifically proven way to slow the process of aging in organisms ranging from yeast to mammals. Now a new study in mice shows that through a similar mechanism, calorie restriction may also slow or prevent Alzheimer's disease.

Calorie-restriction -- consuming 30-percent fewer calories than normal -- is the only scientifically proven way to slow the process of aging in organisms ranging from yeast to mammals. Now a new study in mice shows that through a similar mechanism, calorie restriction may also slow or prevent Alzheimer's disease.

"A decrease in amount of calorie intake might have a causal effect in prevention of Alzheimer's disease," says Giulio Pasinetti, professor of psychiatry and neuroscience at Mount Sinai School of Medicine. He and his team conducted the study in a strain of transgenic mice destined to develop Alzheimer's-like symptoms. The mice that were fed a calorie-restricted diet, mainly by a reduction in their carbohydrate intake, over a period of six months, had fewer disease symptoms than their normal-diet counterparts.

"With this kind of calorie restriction we were able to improve memory function – I would say five-fold times more efficient," says Pasinetti. The amount of beta-amyloid peptides, molecules that cause the build-up of characteristic Alzheimer's plaques, was also much lower in the brains of the mice on the low-calorie diet.

Since calorie restriction has been found to increase the expression of proteins known as sirtuins, Pasinetti and his team tested whether or not one of these proteins could be responsible for the reduction of Alzheimer's symptoms in these mice. As they reported in the Journal of Biological Chemistry, they synthesized a sirtuin called SIRT1 and applied it to brain cells in the laboratory to see whether they'd see similar results to those with calorie restriction.

"Excitingly, we have been able to demonstrate that just the SIRT1 molecule, once re-introduced into brain cells was capable to recapitulate almost the same identical features of calorie restriction," says Pasinetti.

They found that SIRT1 actually works by preventing the cleavage of beta amyloid precursor molecules. If the molecules aren't cleaved, they can't join together to form plaques, keeping Alzheimer's symptoms from appearing. "Through the regulation of SIRT1, we might be in a position to cure the disease," says Pasinetti.

Other mammals, including humans, also have a gene with nearly the same sequence and function as the mouse SIRT1. Pasinetti says that preliminary findings in monkeys confirm these results, which makes it more likely that they'll hold true in people.

Normal lab mouse diets consist of around 20-percent protein, 20-percent fat, and 60-percent carbohydrates. For the purposes of calorie restriction in this experiment, the carbohydrates were the main macronutrient reduced. Pasinetti says that this was important to maintain their general health and prevent the mice from developing insulin-resistance – a precursor to diabetes.

The calorie restriction was initiated between four and five months of age, when the mice were in the first stages of developing Alzheimer-type symptoms. Pasinetti says that this corresponds roughly to the stage of Mild Cognitive Impairment in people, which isn't Alzheimer's yet, but is a high-risk condition for developing it. Since drug intervention at a late stage of the disease is unlikely to ever be successful because of the intensity of damage done, prevention is the main goal.

Although he says it's too soon to know whether calorie restriction can prevent Alzheimer's in people, the results of his studies have already convinced Pasinetti to change his own behavior.

"I decided personally and my family, definitely to have a major reduction in the total amount of food that actually we eat," he says.

While the weight of the evidence is building that drastically cutting calories might just be worth it, eventually it might not prove necessary. Pasinetti says that the ultimate goal is to design a pill that imitates calorie restriction without actually requiring us to eat less – leaving us both with healthy minds and healthy appetites.

Pasinetti's research was published in the July 2006 issue of the Journal of Biological Chemistry. The research was funded by the National Science Foundation, National Institute on Aging, Veteran's Administration, Dana Foundation for Brain Research, Cornell Center for Aging Research, and Atkins Foundation.

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