What Our Ancestors Can Teach Us About Exercise, Alzheimer’s and Human Longevity

Our ancient ancestors’ exercise routines could provide important clues about how best to prevent and treat Alzheimer’s disease and other modern age-related diseases, according to a new paper by two University of Arizona researchers.

The article, featured on the cover of the May issue of the journal Trends in Neurosciences, explores the evolutionary links between physical activity, brain aging and the lifespan of humans, who outlive all other primates.

"This is an effort to try to understand the relationship between exercise and an important genetic risk factor for Alzheimer’s disease and vascular disease, and how the human lifespan evolved, which is a fundamental question that’s been considered in the scientific literature for many years," said UA psychology professor Gene Alexander, who co-authored the paper with David Raichlen, a UA associate professor of anthropology.

While many studies today tout the health benefits of exercise, Alexander and Raichlen consider the link between physical activity and health from an evolutionary perspective, beginning about 2 million years ago. It was around that time that humans made the shift from a more apelike, sedentary lifestyle to a highly active hunter-gatherer lifestyle and began living longer.

During that period, humans likely carried two copies of a genotype known as ApoE4, which is directly linked to higher risk for Alzheimer’s disease and cardiovascular disease. Yet, despite the presence of the problematic gene variation, longer lifespans began to evolve.

"Having this risk allele (ApoE4) is our ancestral condition," Raichlen said. "The lower risk alleles evolved relatively recently, so our question was: How do you evolve a long lifespan when you have this ApoE4 risk allele?"

The answer, Raichlen and Alexander believe, lies in humans’ high level of physical activity 2 million years ago.

"To engage in this hunter-gatherer lifestyle you have to be an aerobically active organism. There’s no way around it. You have to go long distances to find your food," Raichlen said.

"We developed a hypothesis that suggests that exercise may be an important modulating factor that helps to compensate for the negative impact of the (genetic) risk factor for Alzheimer’s and vascular disease, and ultimately might help us to understand why humans are able to live much longer than other primate species," said Alexander, who also teaches in the UA Graduate Interdisciplinary Programs in Neuroscience and Physiological Sciences.

As the human lifestyle today has become increasingly sedentary, this evolutionary link may be important in the development of new prevention therapies and treatments for Alzheimer’s and other age-related diseases, Alexander said.

"We are fundamentally endurance athletes, based on our ancestry. Our recent change, to a more sedentary lifestyle, may have led to a situation where this (ApoE4) genotype has become a problem for us, where it might not have been before," he said.

"With our current tendencies towards less active lifestyles, we need to be thinking about exercise as a potentially important intervention. Considering the evolutionary significance of ApoE4 also gives us some clues about why exercise might be especially important for us."

Today, it has been estimated that about 25 percent of the general U.S. population carries the ApoE4 genotype, and only about 2 percent have two copies of it, putting them at even greater risk for Alzheimer’s or vascular disease. However, the prevalence of the genotype in subgroups of the U.S. population and in some other parts of the world is much higher. 

"There are parts of equatorial Africa where the frequency of the ApoE4 allele is something like 40 percent of the population," Raichlen said, "so thinking about how to use exercise to alter risk around the world is important."

Raichlen has studied in-depth the evolution and effects of physical activity in humans. His research covers a range of topics, including the effects of exercise on happiness, the link between aerobic activity and brain size, the walking patterns of human hunter-gatherers and the role of the runners’ high in human evolution.

Alexander, a member of the UA’s Evelyn F. McKnight Brain Institute and the Arizona Alzheimer’s Consortium, has done extensive research on aging and age-related diseases.

The two came together to explore the connection between their two areas of study by considering research literature in anthropology, brain imaging and neuroscience.

"We’ve generated a new hypothesis from these different scientific literatures that typically don’t cross over," Alexander said. "We are drawing on these different disciplines to look at this question in a new way, and I think it really has important implications for how we understand health issues today. Using what we know about ancestral genotypes, their risks, and how our behaviors evolved over time may help us to gain a better understanding of the underlying mechanisms of Alzheimer’s and age-related cognitive decline."

DHA during pregnancy does not appear to improve cognitive outcomes for children

Although there are recommendations for pregnant women to increase their intake of the omega-3 fatty acid docosahexaenoic acid (DHA) to improve fetal brain development, a randomized trial finds that prenatal DHA supplementation did not result in improved cognitive, problem-solving or language abilities for children at four years of age, according to the study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Maria Makrides, B.Sc., B.N.D., Ph.D., of the South Australian Health and Medical Research Institute, Adelaide, Australia and colleagues conducted longer-term follow-up from a previously published study in which pregnant women received 800 mg/d of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. For the follow-up study, outcomes were assessed at 4 years, a time point when any subtle effects on development should have emerged and can be more reliably assessed.

The majority (91.9 percent) of eligible families (DHA group, n = 313; control group, n = 333) participated in the follow-up. The authors found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (such as memory, reasoning, problem solving) did not differ significantly between groups.

"Our data do not support prenatal DHA supplementation to enhance early childhood development."

(Image: Shutterstock)

Ιn resting brains, Yale researchers see signs of schizophrenia

In an advance that increases hopes of finding biological markers for schizophrenia, Yale researchers have discovered widespread disruption of signals while the brain is at rest in those suffering from the disabling neuropsychiatric disease.

The Yale team used fMRI scans and created a mathematical model that simulates brain activity to discover the disruptions in global signaling — or patterns of neurological activity while the brain is not involved in any particular task. Previously, many researchers had thought that the overall brain activity at rest was mostly “background noise” and not clinically important, said Alan Anticevic, assistant professor in psychiatry at the Yale School of Medicine and senior author of the study, reported online May 5 in the Proceedings of the National Academy of Sciences. “To our knowledge these results provide the first evidence that global whole-brain signals are altered in schizophrenia, calling into question the standard removal of this signal in clinical neuroimaging studies,” Anticevic said.

These novel results have vital and broad implications for neuroimaging, as the search for neuropsychiatric biomarkers that could lead to early intervention and improved patient outcomes remains a prominent focus outlined by the National Institute of Mental Health.

How Does Stress Increase Your Risk for Stroke and Heart Attack?

Scientists have shown that anger, anxiety, and depression not only affect the functioning of the heart, but also increase the risk for heart disease.

Stroke and heart attacks are the end products of progressive damage to blood vessels supplying the heart and brain, a process called atherosclerosis. Atherosclerosis progresses when there are high levels of chemicals in the body called pro-inflammatory cytokines.

It is thought that persisting stress increases the risk for atherosclerosis and cardiovascular disease by evoking negative emotions that, in turn, raise the levels of pro-inflammatory chemicals in the body.

Researchers have now investigated the underlying neural circuitry of this process, and report their findings in the current issue of Biological Psychiatry.

“Drawing upon the observation that many of the same brain areas involved in emotion are also involved in sensing and regulating levels of inflammation in the body, we hypothesized that brain activity linked to negative emotions – specifically efforts to regulate negative emotions – would relate to physical signs of risk for heart disease,” explained Dr. Peter Gianaros, Associate Professor at the University of Pittsburgh and first author on the study.

To conduct the study, Gianaros and his colleagues recruited 157 healthy adult volunteers who were asked to regulate their emotional reactions to unpleasant pictures while their brain activity was measured with functional imaging. The researchers also scanned their arteries for signs of atherosclerosis to assess heart disease risk and measured levels of inflammation in the bloodstream, a major physiological risk factor for atherosclerosis and premature death by heart disease.

They found that individuals who show greater brain activation when regulating their negative emotions also exhibit elevated blood levels of interleukin-6, one of the body’s pro-inflammatory cytokines, and increased thickness of the carotid artery wall, a marker of atherosclerosis.

The inflammation levels accounted for the link between signs of atherosclerosis and brain activity patterns seen during emotion regulation. Importantly, the findings were significant even after controlling for a number of different factors, like age, gender, smoking, and other conventional heart disease risk factors.

“These new findings agree with the popular belief that emotions are connected to heart health,” said Gianaros. “We think that the mechanistic basis for this connection may lie in the functioning of brain regions important for regulating both emotion and inflammation.”

These findings may have implications for brain-based prevention and intervention efforts to improve heart health and protect against heart disease.”

“It is remarkable to see the links develop between negative emotional states, brain circuits, inflammation, and markers of poor physical health,” said Dr. John Krystal, Editor of Biological Psychiatry. “As we identify the key mechanisms linking brain and body, we may be able to also break the cycle through which stress and depression impair physical health.”

(Image: Bigstock)

Migraine Attacks Increase Following Stress

Migraine sufferers who experienced reduced stress from one day to the next are at significantly increased risk of migraine onset on the subsequent day, according to a new study conducted by researchers at the Montefiore Headache Center and Albert Einstein College of Medicine at Yeshiva University. Stress has long been believed to be a common headache trigger. In this study, researchers found that relaxation following heightened stress was an even more significant trigger for migraine attacks. Findings may aid in recommending preventive treatments and behavioral interventions. The study was published online today in Neurology®, the medical journal of the American Academy of Neurology.

Migraine is a chronic condition that affects approximately 38 million Americans. To examine headache triggers, investigators at the Montefiore Headache Center and Einstein conducted a three month electronic daily diary study which captured 2,011 diary records and 110 eligible migraine attacks in 17 participants. The study compared levels of stress and reduction in stress as predictors of headache.

“This study demonstrates a striking association between reduction in perceived stress and the occurrence of migraine headaches,” said study lead author Richard Lipton, M.D., director, Montefiore Headache Center, professor and vice chair of neurology and the Edwin S. Lowe Chair in Neurology, Einstein. “Results were strongest during the first six hours where decline in stress was associated with a nearly five-fold increased risk of migraine onset. The hormone cortisol, which rises during times of stress and reduces pain, may contribute to the triggering of headache during periods of relaxation.”

Data were collected using a custom-programmed electronic diary. Each day participants recorded information about migraine attacks, two types of stress ratings and common migraine triggers, such as hours of sleep, certain foods, drinks and alcohol consumed, and menstrual cycle. They also recorded their mood each day, including feeling happy, sad, relaxed, nervous, lively and bored.

“This study highlights the importance of stress management and healthy lifestyle habits for people who live with migraine,” said Dawn Buse, Ph.D., director, Behavioral Medicine, Montefiore Headache Center, associate professor, Clinical Neurology, Einstein, and study co-author. “It is important for people to be aware of rising stress levels and attempt to relax during periods of stress rather than allowing a major build up to occur. This could include exercising or attending a yoga class or may be as simple as taking a walk or focusing on one’s breath for a few minutes.”

Wiring of retina reveals how eyes sense motion

Online gamers helped researchers map neuron connections involved in detecting direction of moving objects.

A vast project to map neural connections in the mouse retina may have answered the long-standing question of how the eyes detect motion. With the help of volunteers who played an online brain-mapping game, researchers showed that pairs of neurons positioned along a given direction together cause a third neuron to fire in response to images moving in the same direction.

It is sometimes said that we see with the brain rather than the eyes, but this is not entirely true. People can only make sense of visual information once it has been interpreted by the brain, but some of this information is processed partly by neurons in the retina. In particular, 50 years ago researchers discovered that the mammalian retina is sensitive to the direction and speed of moving images. This showed that motion perception begins in the retina, but researchers struggled to explain how.

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Motor cortex shown to play active role in learning movement patterns

Skilled motor movements of the sort tennis players employ while serving a tennis ball or pianists use in playing a concerto, require precise interactions between the motor cortex and the rest of the brain. Neuroscientists had long assumed that the motor cortex functioned something like a piano keyboard.

"Every time you wanted to hear a specific note, there was a specific key to press," says Andrew Peters, a neurobiologist at UC San Diego’s Center for Neural Circuits and Behavior. "In other words, every specific movement of a muscle required the activation of specific cells in the motor cortex because the main job of the motor cortex was thought to be to listen to the rest of the cortex and press the keys it’s directed to press."

But in a study published in this week’s advance online publication of the journal Nature, Peters, the first author of the paper, and his colleagues found that the motor cortex itself plays an active role in learning new motor movements. In a series of experiments using mice, the researchers showed in detail how those movements are learned over time.

"Our finding that the relationship between body movements and the activity of the part of the cortex closest to the muscles is profoundly plastic and shaped by learning provides a better picture of this process," says Takaki Komiyama, an assistant professor of biology at UC San Diego who headed the research team. "That’s important, because elucidating brain plasticity during learning could lead to new avenues for treating learning and movement disorders, including Parkinson’s disease."

With Simon Chen, another UC San Diego neurobiologist, the researchers monitored the activity of neurons in the motor cortex over a period of two weeks while mice learned to press a lever in a specific way with their front limbs to receive a reward.

"What we saw was that during learning, different patterns of activity—which cells are active, when they’re active—were evident in the motor cortex," says Peters. "This ends up translating to different patterns of activity even for similar movements. Once the animal has learned the movement, similar movements are then accompanied by consistent activity. This consistent activity moreover is totally new to the animal: it wasn’t used early in learning even with movements that were similar to the later movement."

"Early on," Peters says, "the animals will occasionally make movements that look like the expert movements they make after learning. The patterns of brain activity that accompany those similar early and late movements are actually completely different though. Over the course of learning, the animal generates a whole new set of activity in the motor cortex to make that movement. In the piano keyboard analogy, that’s like using one key to make a note early on, but a different key to make the same note later."

By Restoring Sense of Touch to Amputees, HAPTIX Seeks to Overcome Physical and Psychological Effects of Upper Limb Loss

To understand the meaning of “proprioception,” try a simple experiment. Close your eyes and lift your right arm above your head. Then, move it down so that it’s parallel to the ground. Make a fist and release it. Move it forward, and then swing it around behind you like you’re stretching. Finally, freeze in place, open your eyes, and look. Is your arm positioned where you thought it would be?

For most people, the answer will be, “Yes.” That’s because your brain and nervous system worked together to move your body according to your intent and processed the sensory feedback to know where your arm was in space despite not being able to visually track it.

For many upper-limb amputees using prosthetic devices, the answer would be, “No.” They wouldn’t have confidence that their device would be where they think it is because current prostheses lack provisions for providing complex tactile and proprioceptive feedback to the user. Without this feedback, even the most advanced prosthetic limbs will remain numb to the user and manipulation functions will be impaired.

DARPA’s new Hand Proprioception and Touch Interfaces (HAPTIX) program seeks to deliver those kinds of naturalistic sensations to amputees, and in the process, enable intuitive, dexterous control of advanced prosthetic devices that substitute for amputated limbs, provide the psychological benefit of improving prosthesis “embodiment,” and reduce phantom limb pain. The program builds on neural-interface technologies advanced during DARPA’s Revolutionizing Prosthetics and Reliable Neural-Interface Technology (RE-NET) programs that made major steps forward in providing a direct and powerful link between user intent and prosthesis control.

HAPTIX aims to achieve its goals by developing interface systems that measure and decode motor signals recorded in peripheral nerves and/or muscles. The program will adapt one of the advanced prosthetic limb systems developed under Revolutionizing Prosthetics to incorporate sensors that provide tactile and proprioceptive feedback to the user, delivered through patterned stimulation of sensory pathways in the peripheral nerve. One of the key challenges will be to identify stimulation patterning strategies that elicit naturalistic sensations of touch and movement. The ultimate goal is to create a fully-implantable device that is safe, reliable, effective, and approved for human use.

“Peripheral nerves are information-rich and readily accessible targets for interfacing with the human nervous system. Research performed under DARPA’s RE-NET program and elsewhere showed that these nerves maintain motor and sensory fibers that previously innervated the amputated limb, and that these fibers remain functional for decades after limb loss,” said Doug Weber, the DARPA program manager. “HAPTIX will try to tap in to these biological communication pathways so that users can control and sense the prosthesis via the same neural signaling pathways used for intact hands and arms.”

In addition to the improved motor performance that restored touch and proprioception would convey to the user, mounting evidence suggests that sensory stimulation in amputees may provide important psychological benefits such as improving prosthesis “embodiment” and reducing the phantom limb pain that is suffered by approximately 80 percent of amputees. For this reason, DARPA seeks the inclusion of psychologists in the multi-disciplinary teams of scientists, engineers, and clinicians proposing to develop the electrodes, algorithms, and electronics technology components for the HAPTIX system. Teams will need to consider how the use of HAPTIX system may impact the user in several important domains including motor and sensory function, psychology, pain, and quality of life.

“We have the opportunity to not only significantly improve an amputee’s ability to control a prosthetic limb, but to make a profound, positive psychological impact,” Weber said. “Amputees view existing prostheses as if they were tools, like a wrench, used only to perform a specific job, so many people abandon their prostheses unless absolutely needed. We believe that HAPTIX will create a sensory experience so rich and vibrant that the user will want to wear his or her prosthesis full-time and accept it as a natural extension of the body. If we can achieve that, DARPA is even closer to fulfilling its commitment to help restore full and natural functionality to wounded service members.”

The program plan culminates with a 12-month, take-home trial of the complete HAPTIX prosthesis system. To aid performers in the completion of the steps necessary to achieve regulatory approvals for human trials, DARPA consulted with the U.S Food and Drug Administration to incorporate regulatory timelines into the program process.

“Once development of the HAPTIX system is complete, we want people to benefit immediately and be able to use their limb all day, every day, and in every aspect of their lives,” Weber said. “The experience needs to be comfortable and easy. Take-home trials are the first step in making that vision a reality.”

If it is successful, the HAPTIX program will create fully-implantable, modular, and reconfigurable neural-interface microsystems that communicate wirelessly with external modules, such as the prosthesis interface link. Because such technology would have broad application and could fuel future medical devices, HAPTIX also plans to fund teams to pursue the science and technology that would support next-generation HAPTIX capabilities.

Full details of the HAPTIX opportunity are available on the Federal Business Opportunities website at: http://go.usa.gov/kyjJ.