Memory is like an anchor, helping us to navigate the world. But as people get older, many of them start to have problems remembering things. They might suddenly begin to get lost in familiar places, ask the same questions over and over again, or have trouble following recipes and instructions. In the worst cases, dementia or Alzheimer’s creep in. We don’t yet have treatments for this kind of age-related memory loss, but one known risk factor is obesity, which affects about a quarter of American adults.
How obesity and age-related memory loss are connected is so far unclear. But one team from Virginia Tech recently received a grant to look into a specific class of proteins that help cells with waste management, tagging other damaged or unneeded proteins for disposal. The research team, led by neuroscientist Tim Jarome, is especially interested in a tag known as K63. Both aging and obesity cause K63 tags to proliferate in the hippocampus, the brain’s memory center, but if you dial back the excess of K63 in rats, their memories recover.
Jarome’s team wants to know whether K63 behaves similarly in obesity and in aging, and whether preventing the excess tagging from happening in the first place can protect against memory loss. If they’re able to find some common molecular mechanism behind both processes, they might be able to identify a target for treatment, a drug that could prevent or slow memory loss and reduce risk of Alzheimer’s and dementia, particularly in people with obesity.
I spoke with Jarome about how obesity changes the biochemistry of the brain, what he wants to learn about K63, and what the Mediterranean diet looks like for rats.
What made you decide to investigate this question of how obesity relates to memory decline in old age?
There’s strong evidence that obesity is associated with memory loss. It’s actually a risk factor for dementia and Alzheimer’s disease. My lab’s always been interested in memory loss and how we can prevent memory loss with age, but we really don’t understand the role that obesity plays. There are few longitudinal mechanistic studies that look at how obesity changes biochemistry in the brain with age and how that could lead to memory loss. We felt that that was an important gap to address. That’s how we got into this—trying to better connect the two and understand the commonalities between them.
What specifically do you want to understand about how obesity changes the biochemistry of the brain?
We’ve found this specific protein in the brain that we’re calling K63; it’s a form of this protein called ubiquitin. A few years ago, we found that K63 is really bad for memory. When you have too much of it in the brain, especially in the hippocampus, which is one of the main regions of the brain that stores memory, your memory is poor. But what’s interesting is that as we age, that K63 protein naturally elevates in the brain, especially in the hippocampus. By the time we’re really old, we have very high levels of it, and it’s associated with memory loss. If we reduce those levels in advanced age, it actually improves memory. What’s interesting is that we see something similar with obesity: Even at young ages, that K63 protein is elevated already. We think this may be a common mechanism between age-related memory loss and obesity-related memory loss.
What does the K63 protein do?
Ubiquitin binds to other proteins. This form of ubiquitin called K63 is a specific form. It has a lot of functions. It binds to a lot of proteins. We don’t know exactly what it’s doing to the proteins it’s binding to, but that’s part of the purpose of our study. We’re going to try to determine its functional significance, which will help us understand what that elevation means—what it’s doing to cellular functioning in the brain.
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What kinds of age-related changes does obesity tend to cause in the brain?
Other researchers have reported that obesity can increase inflammation within the brain, which is something we also see as we age. Inflammation in the cells of the brain is bad because that can start to impact communication between cells. Some other molecules within the brain also change with both obesity and aging, but that doesn’t mean the mechanism is the same. They could be doing different things. One of the issues has always been trying to connect them together.
Why are you doing your study in rats instead of humans?
We can do things that are a bit more mechanistic. We can actually look inside the brains of the rats. They’re a great model because rats are prone to obesity. They’re also prone to memory loss just like humans as we age. In a 2-year-old rat, which is about 70 to 80 years in a human, we see very high levels of this K63 protein. Obese young adult rats, equivalent to 18 to 20 years in a human, also have elevated levels of this protein. We think that obesity is essentially accelerating the increases of this protein in the rats, in turn accelerating brain aging and memory loss. That might be what’s causing the increased risk of dementia and Alzheimer’s disease with obesity.
How does obesity in rats compare to obesity in humans?
They’re just as prone to obesity as a human would be. If you give them the diet that would lead to obesity, they will gladly eat it and become obese. The really interesting fact is that about a third of all humans over the age of 70 are going to have memory loss. Rats are actually about the same. They mimic humans well on both the obesity side and the age-related memory slide, which is why they’re a great model for trying to understand this. Also, the protein we’re looking at is found in every mammal, so it’s the exact same protein in rats as it is in humans.
Another recent study on obesity and age-related memory loss found that a 1 percent reduction in body weight over 18 months in obese human participants dialed back the brain age of these participants by almost nine months. Does that surprise you?
No. The brain is extremely sensitive to obesity in a couple of ways. One, saturated fats and sugar impact brain functioning. Two, parts of the brain are extremely sensitive to the nutrients that you get in your diet. One of the brain regions that responds a lot to saturated fats, for example, is the hippocampus, which is important in forming memories. It’s among the first (region) impacted in Alzheimer’s disease. If you lost body weight over time via a dietary intervention, the brain is going to respond to that dietary intervention because of the change in nutrients that you’re getting, which can improve cellular functioning in some of these brain regions.
There’s some evidence from animal studies, and emerging evidence from human trials, that calorie restriction and intermittent fasting have positive effects on brain aging, improving cognitive function, and reducing risks for neurodegenerative disease. Is there any evidence that this might work through similar pathways as obesity and brain aging?
I don’t know of any evidence yet, but rodent models could be very useful for answering that question, because you can mimic caloric restrictions in different diets and rodent models as well.
For rodent models, how do you mimic, say, a Mediterranean diet?
We call it rat chow. It’s the food that they eat. There are specialized companies that make different nutrient combinations. For example, there’s a diet that contains 60 percent of its kilo-calories from fat. We call it the McDonald’s diet. It’s basically a diet that’s heavy in saturated fat. They gain weight quickly, but there are many other versions. They have a so-called “Western diet.” There’s a huge list that could go on forever. Basically, we control the nutrients they consume, because in any of those diets, it’s really about the nutrients.
What’s your hypothesis about how obesity-induced memory loss and aging-induced memory loss are connected?
My lab has already found that the K63 protein is normally bad for memory. If you have too much of it, then memory’s poor. We’ve also found that if we reduce levels of that protein in older rats, we can restore their memory. We don’t exactly know why yet. Based on our aging work, where we’ve looked at what this K63 protein targets, it seems to be connected to mitochondrial function in cells, which is the energy powerhouse for cells. We think that’s gonna be one of the primary targets for both obesity and aging—but there could be more. 
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Lead image: LIGHTFIELD STUDIOS / Adobe Stock
