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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Functioning of aged brains and muscles in mice made younger

Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.

In two separate papers given early online release today by the journal Science—which is publishing the papers this coming Friday, Professors Amy Wagers, PhD, and Lee Rubin, PhD, of Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice—they could detect smell as younger mice do.

Rubin, and Wagers, who also has a laboratory at the Joslin Diabetes Center, each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years.

Postdoctoral fellow Lida Katsimpardi, PhD, is the lead author on the Rubin group’s paper, and postdocs Manisha Sinha, PhD, and Young Jang, PhD, are the lead authors on the paper from the Wagers group.

Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, MD, of Brigham and Women’s Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.

Doug Melton, PhD, co-chair of HSCRB and co-director of HSCI, reacted to the two papers by saying that he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer: the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” he said.

Melton, Harvard’s Xander University Professor, continued, saying that the ongoing collaboration between Wagers, a stem cell biologist whose focus has been on muscle, Rubin, whose focus is on neurodegenerative diseases and using patient generated stem cells as targets for drug discovery, and Lee, a practicing cardiologist and researcher, “is a perfect example of the power of the Harvard Stem Cell Institute as an engine of truly collaborative efforts and discovery, bringing together people with big, unique ideas and expertise in different biological areas.”

As Melton noted, GDF11 is naturally found in much higher concentrations in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.

Wagers first began using the parabiotic system in mice 14 years ago as a postdoctoral fellow at Stanford University, when she and colleagues Thomas Rando, MD, PhD, of Stanford, Irina Conboy, PhD, of the University of California, Berkley, and Irving Weissman, MD, of Stanford, observed that the blood of young mice circulating in old mice seemed to have some rejuvenating effects on muscle repair after injury.

Last year, she and Richard Lee published a paper in which they reported that when exposed to the blood of young mice, the enlarged, weakened hearts of older mice returned to a more youthful size, and their function improved. And then working with a Colorado firm, the pair reported that GDF11 was the factor in the blood apparently responsible for the rejuvenating effect. That finding has raised hopes that GDF11 may prove, in some form, to be a possible treatment for diastolic heart failure, a fatal condition in the elderly that now is irreversible, and fatal.

“From the previous work it could have seemed that GD11 was heart specific,” said Wagers, “but this shows that it is active in multiple organs and cell types. Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover,” Wagers explained.

She continued: “The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation of DNA damage in muscle stem cells might reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair.”

Wagers noted that there is still a great deal to be learned about the mechanics of aging in muscle, and its repair. “I don’t think we fully understand how this happening or why. We might say that the damage is modification to the genetic material; the genome does have breaks in it. But whether it’s damaging, or a necessary part of repair, we don’t know yet.”

Rubin, whose primary research focus is on developing treatment for neurodegenerative diseases, particularly in children, said that when his group began its GDF11 experiments, “we knew that in the old mouse things were bad in the brain, there is a reduced amount of neurogenesis (the development of neurons), and it’s well known that cognition goes down. It wasn’t obvious to me that those things that can be repaired in peripheral tissue could be fixed in the brain.”

Rubin said that postdoctoral fellow Lida Katsimpardi, the lead author on his group’s paper, was taught the parabiotic experimental technique by Wagers, but conducted the Rubin group’s experiments independently of the Wagers group, and “she saw an increase in neural stem cells, and increased development of blood vessels in the brain.” Rubin said that 3D reconstruction of the brain, and magnetic resonance imaging (MRI) of the mouse brain showed “more new blood vessels and more blood flow,” both of which are normally associated with younger, healthier brain tissue.”

Younger mice, Rubin said, “have a keen sense of olfactory discrimination,” they can sense fine differences in odor. “When we tested the young mice, they avoided the smell of mint; the old mice didn’t. But the old mice exposed to the blood of the young mice, and those treated with GDF11 did.”

“We think an effect of GDF11 is the improved vascularity and blood flow, which is associated with increased neurogenesis,” Rubin said. “However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF11, or GDF11 itself, could” reverse the damage of aging.

“It isn’t out of question that GDF11,” or a drug developed from it, “might be capable of slowing some of the cognitive defects associated with Alzheimer’s disease, a disorder whose main risk factor is aging itself,” Rubin said. It is even possible that this could occur without directly changing the “plaque and tangle burden” that are the pathological hallmarks of Alzheimer’s. Thus, a future treatment for this disease might be a combination of a therapeutic that reduces plaques and tangles, such as an antibody directed against the β-amyloid peptide, with a potential cognition enhancer like GDF11.

Wagers said that the two research groups are in discussions with a venture capital group to obtain funding to “be able to do the additional preclinical work” necessary before moving GDF11 into human trials.

“I would wager that the results of this work, together with the other work, will translate into a clinical trial and a treatment,” said the stem cell biologist. “But of course that’s just a wager.”