Scientists work out the effects of exercise at the cellular level

The health benefits of exercise are well known but new research shows that the body's response to exercise is more complex and far-reaching than previously thought. In a study on rats, a team of scientists from across the United States has found that physical activity causes many cellular and molecular changes in all 19 of the organs they studied in the animals.

Exercise lowers the risk of many diseases, but scientists still don't fully understand how exercise changes the body on a molecular level. Most studies have focused on a single organ, sex, or time point, and only include one or two data types.

To take a more comprehensive look at the biology of exercise, scientists with the Molecular Transducers of Physical Activity Consortium (MoTrPAC) used an array of techniques in the lab to analyze molecular changes in rats as they were put through the paces of weeks of intense exercise. Their findings appear in Nature.

The team studied a range of tissues from the animals, such as the heart, brain, and lungs. They found that each of the organs they looked at changed with exercise, helping the body to regulate the immune system, respond to stress, and control pathways connected to inflammatory liver disease, heart disease, and tissue injury.

The data provide potential clues into many different human health conditions; for example, the researchers found a possible explanation for why the liver becomes less fatty during exercise, which could help in the development of new treatments for non-alcoholic fatty liver disease.

The team hopes that their findings could one day be used to tailor exercise to an individual's health status or to develop treatments that mimic the effects of physical activity for people who are unable to exercise. They have already started studies on people to track the molecular effects of exercise.

Launched in 2016, MoTrPAC draws together scientists from the Broad Institute of MIT and Harvard, Stanford University, the National Institutes of Health, and other institutions to shed light on the biological processes that underlie the health benefits of exercise. The Broad project was originally conceived of by Steve Carr, senior director of Broad's Proteomics Platform; Clary Clish, senior director of Broad's Metabolomics Platform; Robert Gerszten, a senior associate member at the Broad and chief of cardiovascular medicine at Beth Israel Deaconess Medical Center; and Christopher Newgard, a professor of nutrition at Duke University.

Co-first authors on the study include Pierre Jean-Beltran, a postdoctoral researcher in Carr's group at Broad when the study began, as well as David Amar and Nicole Gay of Stanford. Courtney Dennis and Julian Avila, both researchers in Clish's group, were also co-authors on the manuscript.

"It took a village of scientists with distinct scientific backgrounds to generate and integrate the massive amount of high quality data produced," said Carr, a co-senior author of the study. "This is the first whole-organism map looking at the effects of training in multiple different organs. The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration."

The team has made all of the animal data available in an online public repository. Other scientists can use this site to download, for example, information about the proteins changing in abundance in the lungs of female rats after eight weeks of regular exercise on a treadmill, or the RNA response to exercise in all organs of male and female rats over time.

Whole-body analysis

Conducting such a large and detailed study required a lot of planning. "The amount of coordination that all of the labs involved in this study had to do was phenomenal," said Clish.

In partnership with Sue Bodine at the Carver College of Medicine at the University of Iowa, whose group collected tissue samples from animals after up to eight weeks of training, other members of the MoTrPAC team divided the samples up so that each lab -- Carr's team analyzing proteins, Clish's studying metabolites, and others -- would examine virtually identical samples.

"A lot of large-scale studies only focus on one or two data types," said Natalie Clark, a computational scientist in Carr's group. "But here we have a breadth of many different experiments on the same tissues, and that's given us a global overview of how all of these different molecular layers contribute to exercise response."

In all, the teams performed nearly 10,000 assays to make about 15 million measurements on blood and 18 solid tissues. They found that exercise impacted thousands of molecules, with the most extreme changes in the adrenal gland, which produces hormones that regulate many important processes such as immunity, metabolism, and blood pressure. The researchers uncovered sex differences in several organs, particularly related to the immune response over time. Most immune-signaling molecules unique to females showed changes in levels between one and two weeks of training, whereas those in males showed differences between four and eight weeks.

Some responses were consistent across sexes and organs. For example, the researchers found that heat-shock proteins, which are produced by cells in response to stress, were regulated in the same ways across different tissues. But other insights were tissue-specific. To their surprise, Carr's team found an increase in acetylation of mitochondrial proteins involved in energy production, and in a phosphorylation signal that regulates energy storage, both in the liver that changed during exercise. These changes could help the liver become less fatty and less prone to disease with exercise, and could give researchers a target for future treatments of non-alcoholic fatty liver disease.

"Even though the liver is not directly involved in exercise, it still undergoes changes that could improve health. No one speculated that we'd see these acetylation and phosphorylation changes in the liver after exercise training," said Jean-Beltran. "This highlights why we deploy all of these different molecular modalities -- exercise is a very complex process, and this is just the tip of the iceberg."

"Two or three generations of research associates matured on this consortium project and learned what it means to carefully design a study and process samples," added Hasmik Keshishian, a senior group leader in Carr's group and co-author of the study. "Now we are seeing the results of our work: biologically insightful findings that are yielding from the high quality data we and others have generated.That's really fulfilling."

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Does the time of day you move your body make a difference to your health?

Undertaking the majority of daily physical activity in the evening is linked to the greatest health benefits for people living with obesity, according to researchers from the University of Sydney, Australia who followed the trajectory of 30,000 people over almost 8 years.

Using wearable device data to categorise participant's physical activity by morning, afternoon or evening, the researchers uncovered that those who did the majority of their aerobic moderate to vigorous physical activity- the kind that raises our heartrate and gets us out of breath- between 6pm and midnight had the lowest risk of premature death and death from cardiovascular disease.

The frequency with which people undertook moderate to vigorous physical activity (MVPA) in the evening, measured in short bouts up to or exceeding three minutes, also appeared to be more important than their total amount of physical activity daily.

The study, led by researchers from the University's Charles Perkins Centre is published in the journal Diabetes Care today.

"Due to a number of complex societal factors, around two in three Australians have excess weight or obesity which puts them at a much greater risk of major cardiovascular conditions such as heart attacks and stroke, and premature death," said Dr Angelo Sabag, Lecturer in Exercise Physiology at the University of Sydney.

"Exercise is by no means the only solution to the obesity crisis, but this research does suggest that people who can plan their activity into certain times of the day may best offset some of these health risks."

Smaller clinical trials have shown similar results, however the large scale of participant data in this study, the use of objective measures of physical activity and hard outcomes, such as premature death, makes these findings significant.

Joint first author Dr Matthew Ahmadi also stressed that the study did not just track structured exercise. Rather researchers focused on tracking continuous aerobic MVPA in bouts of 3 minutes or more as previous research shows a strong association between this type of activity, glucose control and lowered cardiovascular disease risk compared with shorter (non-aerobic) bouts.

"We didn't discriminate on the kind of activity we tracked, it could be anything from power walking to climbing the stairs, but could also include structured exercise such as running, occupational labour or even vigorously cleaning the house," said Dr Ahmadi, National Heart Foundation postdoctoral research fellow at the Charles Perkins Centre, University of Sydney.

While observational, the findings of the study support the authors original hypothesis, which is the idea -- based on previous research -- that people living with diabetes or obesity, who are already glucose intolerant in the late evening, may be able to offset some of that intolerance and associated complications, by doing physical activity in the evening.

The researchers used data from UK Biobank and included 29,836 adults aged over 40 years of age living with obesity, of whom 2,995 participants were also diagnosed with Type 2 diabetes.

Participants were categorised into morning, afternoon of evening MVPA based on when they undertook the majority of their aerobic MVPA as measured by a wrist accelerometer worn continuously for 24 hours a day over 7 days at study onset.

The team then linked health data (from the National Health Services and National Records of Scotland) to follow participants health trajectory for 7.9 years. Over this period they recorded 1,425 deaths, 3,980 cardiovascular events and 2,162 microvascular disfunction events.

To limit bias, the researchers accounted for differences such as age, sex, smoking, alcohol intake, fruit and vegetable consumption, sedentary time, total MVPA, education, medication use and sleep duration. They also excluded participants with pre-existing cardiovascular disease and cancer.

The researchers say the length of the study follow-up and additional sensitivity analysis bolster the strength of their findings however, due to the observational design, they cannot completely rule out potential reverse causation. This is the possibility that some participants had lower aerobic MVPA levels due to underlying or undiagnosed disease.

Professor Emmanuel Stamatakis, Director of the Mackenzie Wearables Research Hub at the Charles Perkins Centre and senior author on the paper, said the sophistication of studies in the wearables field is providing huge insights into the patterns of activity that are most beneficial for health.

"It is a really exciting time for researchers in this field and practitioners alike, as wearable device-captured data allow us to examine physical activity patterns at a very high resolution and accurately translate findings into advice that could play an important role in health care," said Professor Stamatakis.

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Heart health tip for older adults in 2023: Step it up a bit

The evidence-based health benefits of walking continue to accumulate, according to ongoing research by a University of Massachusetts Amherst physical activity epidemiologist, who leads an international consortium known as the Steps for Health Collaborative.

Findings from the latest study led by Amanda Paluch, assistant professor of kinesiology in the School of Public Health and Health Sciences, show that older adults who walked between 6,000 and 9,000 steps per day had a 40-50% reduced risk of a cardiovascular event, such as a heart attack or stroke, compared to those who walked 2,000 steps per day.

"We found for adults over 60, there was a strikingly lower risk of a cardiovascular event or disease over an average follow-up of six years," says Paluch, whose team's research was published this week in the journal Circulation. "When accumulating more steps per day, there was a progressively lower risk."

Earlier this year, research by Paluch and the Steps for Health Collaborative showed that more movement, even below the highly touted but unscientific "10,000 steps per day," was associated with longevity benefits. The meta-analysis of 15 studies involving nearly 50,000 people from four continents found that walking between 6,000 and 8,000 steps per day was linked with a lower risk of death from all causes among older adults.

Following those findings, Paluch and team wanted to tackle the less-charted territory of steps per day and cardiovascular disease. The results were similar, in terms of the most beneficial range of steps.

While there appears to be a continual additional benefit for those who walk more than 6,000 steps, Paluch says, encouraging the least-active older adults to take more steps is perhaps the most important public health message.

"The people who are the least active have the most to gain," she says. "For those who are at 2,000 or 3,000 steps a day, doing a little bit more can mean a lot for their heart health. If you're at 6,000 steps, getting to 7,000 and then to 8,000 also is beneficial, it's just a smaller, incremental improvement."

The meta-analysis of eight studies involved more than 20,000 people from the U.S. and 42 other countries. For younger adults, no link between steps per day and cardiovascular risk was detected.

"This is because cardiovascular disease is a disease of aging and often doesn't come to fruition until we're at older ages," says Paluch, whose project was supported by the Centers for Disease Control and Prevention (CDC). "You're not going to see many people develop cardiovascular disease after six years of follow-up in young to middle adulthood."

Future research involving younger adults and steps per day would focus on the precursors of cardiovascular disease, including high blood pressure, obesity and type 2 diabetes. "Those conditions develop in younger adults and are important for early prevention," Paluch says.

Four of the eight studies the researchers analyzed included data about walking intensity, or how fast the steps were taken. "We're interpreting these results with caution, but we did not find any striking association with walking intensity," she says. "There was no additional benefit with how fast you're walking, beyond the total number of steps that you accumulated."

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Beer hops compounds could help protect against Alzheimer's disease

Beer is one of the oldest and most popular beverages in the world, with some people loving and others hating the distinct, bitter taste of the hops used to flavor its many varieties. But an especially "hoppy" brew might have unique health benefits. Recent research published in ACS Chemical Neuroscience reports that chemicals extracted from hop flowers can, in lab dishes, inhibit the clumping of amyloid beta proteins, which is associated with Alzheimer's disease (AD).

AD is a debilitating neurodegenerative disease, often marked by memory loss and personality changes in older adults. Part of the difficulty in treating the disease is the time lag between the start of underlying biochemical processes and the onset of symptoms, with several years separating them. This means that irreversible damage to the nervous system occurs before one even realizes they may have the disease. Accordingly, preventative strategies and therapeutics that can intervene before symptoms appear are of increasing interest.

One of these strategies involves "nutraceuticals," or foods that have some type of medicinal or nutritional function. The hop flowers used to flavor beers have been explored as one of these potential nutraceuticals, with previous studies suggesting that the plant could interfere with the accumulation of amyloid beta proteins associated with AD. So, Cristina Airoldi, Alessandro Palmioli and colleagues wanted to investigate which chemical compounds in hops had this effect.

To identify these compounds, the researchers created and characterized extracts of four common varieties of hops using a method similar to that used in the brewing process. In tests, they found that the extracts had antioxidant properties and could prevent amyloid beta proteins from clumping in human nerve cells. The most successful extract was from the Tettnang hop, found in many types of lagers and lighter ales. When that extract was separated into fractions, the one containing a high level of polyphenols showed the most potent antibiotic and aggregation-inhibiting activity. It also promoted processes that allow the body to clear out misfolded, neurotoxic proteins. Finally, the team tested the Tettnang extract in a C. elegans model and found that it protected the worms from AD-related paralysis, though the effect was not very pronounced. The researchers say that although this work may not justify drinking more bitter brews, it shows that hop compounds could serve as the basis for nutraceuticals that combat the development of AD.

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Multiple health benefits of b-type procyanidin-rich foods like chocolate and apples consumed in right amounts

B-type procyanidins, made of catechin oligomers, are a class of polyphenols found abundantly in foods like cocoa, apples, grape seeds, and red wine. Several studies have established the benefits of these micronutrients in reducing the risk of cardiovascular diseases and strokes. B-type procyanidins are also successful in controlling hypertension, dyslipidemia, and glucose intolerance. Studies attest to the physiological benefits of their intake on the central nervous system (CNS), namely an improvement in cognitive functions. These physiological changes follow a pattern of hormesis -- a phenomenon in which peak benefits of a substance are achieved at mid-range doses, becoming progressively lesser at lower and higher doses.

The dose-response relationship of most bioactive compounds follows a monotonic pattern, in which a higher dose shows a greater response. However, in some exceptional cases, a U-shaped dose-response curve is seen. This U-shaped curve signifies hormesis -- an adaptive response, in which a low dose of usually a harmful compound induces resistance in the body to its higher doses. This means that exposure to low levels of a harmful trigger can induce the activation of stress-resistant pathways, leading to greater repair and regeneration capabilities. In case of B-type procyanidins, several in vitro studies support their hormetic effects, but these results have not been demonstrated in vivo.

To address this knowledge gap, researchers from Shibaura Institute of Technology (SIT), Japan, led by Professor Naomi Osakabe from the Department of Bioscience and Engineering, reviewed the data from intervention trials supporting hormetic responses of B-type procyanidin ingestion. The team, comprising Taiki Fushimi and Yasuyuki Fujii from the Graduate School of Engineering and Science (SIT), also conducted in vivo experiments to understand possible connections between B-type procyanidin hormetic responses and CNS neurotransmitter receptor activation. Their article was made available online on June 15, 2022 and has been published in volume 9 of Frontiers of Nutrition on September 7, 2022.

The researchers noted that a single oral administration of an optimal dose of cocoa flavanol temporarily increased the blood pressure and heart rate in rats. But the hemodynamics did not change when the dose was increased or decreased. Administration of B-type procyanidin monomer and various oligomers produced similar results. According to Professor Osakabe, "These results are consistent with those of intervention studies following a single intake of food rich in B-type procyanidin, and support the U-shaped dose-response theory, or hormesis, of polyphenols."

To observe whether the sympathetic nervous system (SNS) is involved in the hemodynamic changes induced by B-type procyanidins, the team administered adrenaline blockers in test rats. This successfully decreased the temporary increase in heart rate induced by the optimal dose of cocoa flavanol. A different kind of blocker -- a1 blocker -- inhibited the transient rise in blood pressure. This suggested that the SNS, which controls the action of adrenaline blockers, is responsible for the hemodynamic and metabolic changes induced by a single oral dose of B-type procyanidin.

The researchers next ascertained why optimal doses, and not high doses, are responsible for the thermogenic and metabolic responses. They co-administered a high dose of cocoa flavanol and yohimbine (an α2 blocker) and noted a temporary but distinct increase in blood pressure in test animals. Similar observations were made with the use of B-type procyanidin oligomer and yohimbine. Professor Osakabe surmises, "Since α2 blockers are associated with the down-regulation of the SNS, the reduced metabolic and thermogenic outputs at a high dose of B-type procyanidins seen in our study may have induced α2 auto-receptor activation. Thus, SNS deactivation may be induced by a high dose of B-type procyanidins."

Previous studies have proven the role of the gut-brain axis in controlling hormetic stress-related responses. The activation of the hypothalamus-pituitary-adrenal (HPA) axis by optimal stress has a strong influence on memory, cognition, and stress tolerance. This article highlights how HPA activation occurs after a single dose of B-type procyanidin, suggesting that stimulation with an oral dose of B-type procyanidin might be a stressor for mammals and cause SNS activation.

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Lager beer, whether it contains alcohol or not, could help men's gut microbes

Like wine, beer can have health benefits when consumed in moderation. Non-alcoholic beers have become wildly popular recently, but are these drinks also healthful? In a pilot study, researchers in ACS' Journal of Agricultural and Food Chemistry report that compared to their pre-trial microbiome, men who drank either one alcoholic or non-alcoholic lager daily had a more diverse set of gut microbes, which can reduce the risk for some diseases.

Trillions of microorganisms line human gastrointestinal tracts, directly impacting their host's well-being. Studies have shown that when more types of bacteria are present, people tend to have a lower chance of developing chronic diseases, such as heart disease and diabetes. And beer contains compounds, such as polyphenols, as well as microorganisms from its fermentation, that could impact the variety of microbes in the human gut. A previously published "cross-over" study showed that when both men and women consumed non-alcoholic lager beer for 30 days, their gut microbiome diversity increased. Many of those same people were also in a second group that drank an alcoholic version of the beer, and it didn't have the same effect. Few other clinical trials have tested this issue, so Ana Faria and colleagues wanted to see if they would find similar results with men in a different type of study -- a parallel, randomized trial design -- with two separate groups of participants.

In this double-blind study, 19 healthy men were randomly divided into two groups who drank 11 fluid ounces of either alcoholic or non-alcoholic lager with dinner for 4 weeks. The researchers found that the participants' weight, body mass index and serum markers for heart health and metabolism didn't change during the study. But at the end of the 4-week period, both groups had greater bacterial diversity in their gut microbiome and higher levels of fecal alkaline phosphatase, indicating an improvement in intestinal health. The researchers suggest that these results could differ from those of the prior study because of the different designs of the trials, and because the participants were living in different communities. But based on this pilot study, the researchers say that consuming one bottle of beer, regardless of its alcohol content, may be beneficial to the gut microbiome and intestinal health of men. However, they add that because the safest level of alcohol consumption is none, non-alcoholic beer may be the more healthful choice.

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