Professor investigates how that cheeseburger affects your memory down the road

July 24, 2019
Kumar Sambamurti poses in his lab
Kumar Sambamurti is investigating whether restricting foods with certain amino acids can forestall dementia. Photos by Sarah Pack

“All food is poison at some stage,” Kumar Sambamurti, Ph.D., says cheerfully. 

The College of Medicine professor is studying how the typical American diet affects the development of Alzheimer’s disease. He’s looking at one amino acid in particular – methionine, which is found in many foods but especially in eggs, fish and meat.

Methionine is an essential amino acid, necessary for growth and tissue repair. But just as water is necessary to life but will kill you if you take in too much, too much of this amino acid has been linked to diabetes, heart disease, cancer, schizophrenia and memory impairment. A Western-style diet, heavy on the foods that are laden with this amino acid, is probably overwhelming to the body’s methionine-homocysteine turnover machinery, he says.

“If you are young, any methionine you are overeating degraded very rapidly, and it’s converted to energy. But if you’re not able to do that, then there’s probably a buildup of amino acids,” he says. “The problem is not the toxic protein. The problem is the protein was never supposed to accumulate to that level.”

He thinks that a diet that restricts methionine, or one that alternates between restricting methionine and other essential amino acids like leucine, could prevent the development of Alzheimer’s by stabilizing the amount of protein in the cells and by preventing compensation by microbiota in the gut.

He points out that the plaques and tangles in the brain that have long been associated with Alzheimer’s actually start to show up in middle age, well before people show signs of dementia. These plaques and tangles, first discovered by German psychiatrist and neuropathologist Alois Alzheimer in 1906, are composed of proteins that clump together inside and between the brain’s neurons. Research to find a drug that will reduce existing plaques or tangles has been disappointing. Sambamurti thinks that taking a preventive approach is a better way.

“All of cancer has had so much progress, but most of the progress has really been prevention,” he says. “It’s been recognizing that cigarette smoking causes lung cancer so you shouldn’t do it, that fiber is needed in the diet for preventing colon cancer.”

Similarly, people concerned about Alzheimer’s disease, especially those with genetic risk factors, might think, “I don’t want to push my protein synthesis into overdrive, so I’m creating some limiting factors every day,” he says.

Kumar Sambamurti works in his lab 
Dr. Sambamurti in the lab.

Sambamurti received a $411,000 grant from the National Institute on Aging to investigate the impact of methionine restriction further. He says his interest was piqued when he realized that in cell cultures that were starved of methionine, the amount of plaque protein secreted – the parts that cause trouble in the brain – was reduced after 24 hours. In addition, the original protein – the one that gave rise to the plaque protein – had stabilized. It seemed the cells were sensing the lack of incoming methionine and responding by slowing down protein turnover to compensate for reduced synthesis. And when he tried methionine restriction in animal models, he found a marked improvement in cognition. “I haven’t seen such beautiful improvement in behavior with anything else,” he said.

But Sambamurti also wants to determine how the microbiome comes into play. Trillions of bacteria, fungi, parasites and viruses live within the human gut, influencing the health of their human host. Researchers have begun an intense focus on the microbiome in the past decade, though scientists have been aware of its existence much longer.

Sambamurti recalled a lecture he attended in the 1980s by V.I. Mathan, a general physician from India, who spoke about the phenomenon of vegetarian Indians who migrated to England becoming B12 deficient. B12 is a vitamin found in dairy products, eggs, fish, meat and poultry – foods the Indians wouldn’t eat either in India or in England.

“It is possible that in India, these individuals have a bacterial flora in the small intestine which provides a significant proportion of their daily requirements of vitamin B 12, but when they move to a more protected environment the bacterial flora reverts to that characteristic of subjects living in Western countries with little or no resident flora in the upper small bowel, the individuals lose their endogenous source of vitamin B 12 and therefore become more prone to develop overt vitamin B 12 deficiency,” Mathan and colleagues had written in a 1980 paper in the journal Nature.

In other words, for the vegetarians living in India, the bacteria in their microbiomes were making up for the B12 that they weren’t getting through their diets. Sambamurti wondered if something similar might happen with methionine if he began purposefully restricting the amino acid. He turned to his colleague Chenthamarakshan Vasu, Ph.D., an associate professor in the College of Medicine, whose research focuses on understanding the intestinal microbiota and host interaction. Microbes in our gut compensate to a certain extent for deficiencies in our diet, Vasu says. That’s how different cultures from around the world can eat such different diets and yet still survive.

In regard to Sambamurti’s research, Vasu said they wanted to see what changes would happen to the gut microbial composition when methionine was restricted. Microbes produce amino acids, though not to the same extent as those that come from the food sources people ingest, he says. There’s still much research to be done, as the microbial-produced amino acids might be delivered to the human host at a different rate and could be mixed with microbial metabolism byproducts that also turn out to be beneficial to the host, he says.

But if a person wants to restrict methionine in the hopes of avoiding excess protein buildup in the brain, and the microbiome responds to this restriction by producing its own methionine, then the microbes are working at cross-purposes to what the host is trying to do, Sambamurti says. Thus, he explained, he’s investigating an alternating diet in which different amino acids are restricted each week as a way to confuse the microbes so they’re not fighting the purposeful amino acid restriction.

Sambamurti can envision a day in which people would get their amino acid levels checked to look for abnormal accumulation in the same way they currently get cholesterol checks, and then could respond by adjusting their diet to hopefully stave off Alzheimer’s and other neurodegenerative diseases linked to misfolding and accumulation of proteins.

Ultimately, he says, we need to think about food in a more medically therapeutic way, and figuring out the best diet for people will be a research field of its own. But, he added, there are many possibilities out there.

“I don’t think we need to go back to the ‘60s diet. Now that we are living in so much more of an international world, there are hundreds of cuisines to evaluate to select ones that actually work best and combine them to obtain the best outcome,” he says.

 

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Leslie Cantu

Keywords: Research