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Scientists have long assumed Alzheimer’s Disease begins in the brain. But what if it’s a whole-body illness, and the brain is just where we notice it the most?

“Since Alzheimer’s Disease was first identified, more than 100 years ago, we’ve thought about it as a disease of the brain,” said Constanza Cortes, an assistant professor at the Leonard Davis School of Gerontology. “But recently we’ve come to appreciate that it may be a disease of the body and the brain is just the most sensitive organ to it.”

In fact, researchers say, there’s growing evidence that what ails the mind might begin in the body. From studying the Mediterranean diet to tracking exercise and monitoring biofeedback, USC scientists are examining how our brains react to the ways we eat and move and manage stress.

Something as simple as the foods we consume may ward off depression according to a 2020 paper by Leonard Davis school instructional associate professor Roberto Vicinanza and others. The study examined Mediterranean diet adherence in 143 older people with chronic diseases at a geriatric clinic in Rome. The results add to accumulating evidence that the Mediterranean diet may not only promote positive mental health but also may protect older people — even those struggling with other health issues — from symptoms of depression. The traditional Mediterranean diet is characterized by a high consumption of fruits and vegetables, legumes, extra virgin olive oil and nuts, a moderate amount of fish, and a low amount of dairy and meat products.

“The Mediterranean diet seems to play a crucial role in mediating the relationship between the presence of multiple chronic conditions and depressive symptoms, suggesting that this diet can play a role in protecting mental health,” Vicinanza said. “Although depression is not considered part of the normal aging process. It can affect older individuals with multiple health issues with a significant impact on the clinical outcomes and the quality of life.”

In addition to eating right, maintaining a regular exercise regimen may also stave off aging in the brain.

“No matter what markers of brain health we look at, those aging populations that are sedentary tend to do worse than those that are physically active,” Cortes said.

The problem for many older people, Cortes said, is that as they age, it becomes harder and harder to exercise at the level recommended: at least 150 minutes to 300 minutes at moderate-intensity a week. Sometimes this is because of other medical conditions or injuries, but it can also be due to financial constraints or just accessibility – can someone afford to join a gym? Or can they afford a gym but can’t drive and have no easy way of getting there?

Of course, she added, whatever exercise anyone can do, for however long they can do it, is better than nothing at all. “Start exercising as soon as you can,” she said, “and today is a good day to start.”

But the research holy grail is medication that would mimic at least some of the best effects of exercise, for those who for whatever reason don’t work out. “What we are trying to figure out is can we design exercise in a pill, to allow [people] to receive the benefit of exercise without having to get on a treadmill three times a week?” Cortes said.

To do this, researchers need to better understand how different parts of the body communicate with the brain during exercise. For instance, how do the muscles that attach to our bones (our skeletal muscles) send messages to the brain, and what do those messages trigger? “During exercise, skeletal muscle secretes messages into the blood circulation, and we believe those messages are essentially talking to the brain and telling it to do better,” Cortes said. “If we can identify those messages, then we can probably deliver them in the form of medication and therapy.”

This effort is part of a field of research that’s only been around for about five years, called “exerkines.” That’s short for exercise associated cytokines, which are small proteins and other metabolites (factors) important in cell signaling. Exerkines research encompasses a number of fields, which are often studied separately: exercise, medicine, skeletal muscle physiology and neurobiology, Cortes said.

Through this research, it’s becoming clear that the brain is far from isolated from the rest of the body. “Despite the fact that the brain resides behind the blood-brain barrier, it’s actually in direct communication and conversations with the rest of the body,” Cortes said. “And so, in our lab, we truly believe that skeletal muscle can influence the rate at which the brain ages or develops things like Alzheimer’s Disease.”

Ryo Sanabria suspects bodily stress may also impact brain health. The USC Leonard Davis assistant professor studies how organisms respond to stress at a cellular level. For instance, younger people have greater tolerance for heat than older people do. This is called stress resilience, and it declines as we age.

“So if we just boost stress resilience, will that make aging slow down?” they said. “Or will it reverse aging? Or reverse some aspects of aging? That’s the big question that my lab has tried to answer.”

Boosting stress resilience could look like a pill people could take, or it could be a regimen of repeated, low-grade exposures to certain stresses, they said. In Sanabria’s lab, researchers have tested genes from both worms and humans to learn more about the proteins that combat stress at the cellular level. Since coming to the Leonard Davis School, with its strong focus on Alzheimer’s research, they’ve also begun to compare tissue from the brains of deceased Alzheimer’s patients, with tissue from people who died of other causes. By looking at which specific genes are turned on in the tissues of the Alzheimer’s patients, and comparing that to the control group, their lab is hoping to learn how, or even to what degree, Alzheimer’s is characterized by an inadequate response to stress.

“It’s kind of a backwards method where the person has already died, we have this brain, we can’t do an intervention, but at least we can ask the question: is higher stress resilience associated with not getting Alzheimer’s Disease when you’re 65 plus, and then is having low stress resilience associated with having Alzheimer’s Disease, if all other factors, for example, gender, and genetics are identical?” Sanabria said. “And then, if we can get those answers, we can start thinking about, okay, how can we apply interventions?”

In related research, USC Leonard Davis School Professor Mara Mather published a paper this spring showing that volunteers who followed a routine of simple breathing exercises lowered the levels in their blood of a peptide associated with Alzheimer’s Disease. The volunteers’ slow in-breaths and out-breaths stimulated their parasympathetic nervous systems, which protects against biological stress.

From analyzing what we eat, to how we work out and process physical stressors, USC scientists are changing the way we think about how bodies age and how that aging impacts our brains. Their research is revealing and what steps we can take to improve our physical, cognitive and mental health today and holds promise for future therapies to prevent or treat age-related diseases and promote healthier aging.

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