Exercise cure for COVID-19 complications

•How increasing physical activity, vitamin D, olive leaf, plant protein, flour made from mealworms
could be used to treat long COVID-induced diabetes, depression, hypertension, cancer, osteoarthritis

Scientists have demonstrated how increasing physical activity, vitamin D, olive leaf, plant protein and flour made from mealworms could be used to treat long COVID-induced diabetes, hypertension, depression and pains as well as slow down breast cancer growth.

According to the first study published in the journal Exercise and Sport Sciences Reviews, while no medically recognised treatment exists for Long COVID, exercise may break the vicious cycle of inflammation that can lead to developing diabetes and depression months after a person recovers from the virus.

A research scientist at Pennington Biomedical Research Centre, a campus of Louisiana State University, United States, Dr. Candida Rebello, said: “We know that Long COVID causes depression, and we know that it can increase blood glucose levels to the point where people develop diabetic ketoacidosis, a potentially life-threatening condition common among people with type 1 diabetes.

“Exercise can help. Exercise takes care of the inflammation that leads to elevated blood glucose and the development and progression of diabetes and clinical depression.”

It is unclear how many people suffer from Long COVID. But estimates range from 15 percent to 80 percent of the people infected. Based on those figures, it is possible that as many as one million of Louisiana’s residents suffer from Long COVID.

Long COVID causes what the United State Centre for Disease Control describes as “a constellation of other debilitating symptoms” including brain fog, muscle pain, and fatigue that can last for months after a person recovers from the initial infection.

“For example, a person may not get very sick from COVID-19, but six months later, long after the cough or fever is gone, they develop diabetes,” Rebello said.

One solution is exercise. Rebello and her co-authors describe their hypothesis in “Exercise as a Moderator of Persistent Neuroendocrine Symptoms of COVID-19,” published in the journal Exercise and Sport Sciences Reviews.

Rebello said: “You don’t have to run a mile or even walk a mile at a brisk pace. Walking slowly is also exercising. Ideally, you would do a 30-minute session of exercise. But if you can only do 15 minutes at a time, try to do two 15-minute sessions. If you can only walk 15 minutes once a day, do that. The important thing is to try. It doesn’t matter where you begin. You can gradually build up to the recommended level of exercise.”

Pennington Biomedical Executive Director, who is also a co-author of the paper, Dr. John Kirwan, said: “We know that physical activity is a key component to a healthy life. This research shows that exercise can be used to break the chain reaction of inflammation that leads to high blood sugar levels, and then to the development or progression of type 2 diabetes.”

Also, a large study published online in the British Journal of Sports Medicine found that physical inactivity is linked to more severe COVID-19 infection and a heightened risk of dying from the disease.

Patients with COVID-19 who were consistently inactive during the two years preceding the pandemic were more likely to be admitted to hospital, to require intensive care, and to die than were patients who had consistently met physical activity guidelines, the findings show.

As a risk factor for severe disease, physical inactivity was surpassed only by advanced age and a history of organ transplant.

Several risk factors for severe COVID-19 infection have been identified, including advanced age, male sex, and certain underlying medical conditions, such as diabetes, obesity, and cardiovascular disease.

The researchers said physical inactivity is not one of them, even though it is a well-known contributory risk factor for several long-term conditions, including those associated with severe COVID-19. To explore its potential impact on the severity of the infection, including hospital admission rates, need for intensive care, and death, the researchers compared these outcomes in 48,440 adults with confirmed COVID-19 infection between January and October 2020.

The patients’ average age was 47; nearly two thirds were women (62 per cent). Their average weight (BMI) was 31, which is classified as obese.

Around half had no underlying conditions, including diabetes, COPD, cardiovascular disease, kidney disease, and cancer; nearly one in five (18 per cent) had only one; and almost a third (32 per cent) had two or more.

All of them had reported their level of regular physical activity at least three times between March 2018 and March 2020 at outpatient clinics. This was classified as consistently inactive (0-10 minutes/week); some activity (11-149 minutes/week); or consistently meeting physical activity guidelines (150+ minutes/week).

Some seven per cent were consistently meeting physical activity guidelines; 15 per cent were consistently inactive, with the remainder reporting some activity. White patients were most likely to consistently meet physical activity guidelines (10 per cent), followed by Asian patients (seven per cent), Hispanic patients (six per cent) and African-American patients (five per cent). Some nine per cent of the total were admitted to hospital; around three per cent required intensive care; and two per cent died. Consistently meeting physical activity guidelines was strongly associated with a reduced risk of these outcomes.

After taking account of potentially influential factors, such as race, age, and underlying medical conditions, patients with COVID-19 who were consistently physically inactive were more than twice as likely to be admitted to hospital as those who clocked up 150 plus minutes of physical activity every week.

They were also 73 per cent more likely to require intensive care, and 2.5 times more likely to die of the infection.

And patients who were consistently inactive were also 20 per cent more likely to be admitted to hospital, 10 per cent more likely to require intensive care, and 32 per cent more likely to die of their infection than were patients who were doing some physical activity regularly.

This is an observational study, and as such, can’t establish cause. The study also relied on patients’ own assessments of their physical activity. Nor was there any measure of exercise intensity beyond the threshold of ‘moderate to strenuous exercise’ (such as a brisk walk).

But the study was large and ethnically diverse. And the researchers point out: “It is notable that being consistently inactive was a stronger risk factor for severe COVID-19 outcomes than any of the underlying medical conditions and risk factors identified except for age and a history of organ transplant.

“In fact, physical inactivity was the strongest risk factor across all outcomes, compared with the commonly cited modifiable risk factors, including smoking, obesity, diabetes, hypertension high blood pressure, cardiovascular disease and cancer.”

They concluded: “We recommend that public health authorities inform all populations that short of vaccination and following public health safety guidelines such as social distancing and mask use, engaging in regular physical activity may be the single most important action individuals can take to prevent severe COVID-19 and its complications, including death.

“This message is especially important given the increased barriers to achieving regular [physical activity] during lockdowns and other pandemic restrictions.”

Also, exercise training may slow tumour growth and improve outcomes for females with breast cancer – especially those treated with immunotherapy drugs – by stimulating naturally occurring immune mechanisms, researchers at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) have found.

Tumours in mouse models of human breast cancer grew more slowly in mice put through their paces in a structured aerobic exercise programme than in sedentary mice, and the tumors in exercised mice exhibited an increased anti-tumor immune response.

Co-corresponding author, deputy director of the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH, Dr. Dai Fukumura, said: “The most exciting finding was that exercise training brought into tumours immune cells capable of killing cancer cells known as cytotoxic T lymphocytes (CD8+ T cells) and activated them. With more of these cells, tumors grew more slowly in mice that performed exercise training.”

As Fukumura and colleagues report in the journal Cancer Immunology Research, the beneficial effects of exercise training are dependent on CD8+ T cells; when the researchers depleted these cells in mice, tumors in mice that exercised no longer grew at a slower rate.

They also found evidence that recruitment of CD8+ T cells to tumors was dependent on two chemical recruiters (chemokines) labeled CXCL9 and CXCL11. Levels of these chemokines were increased in mice that exercised, and mice that were genetically engineered to lack the receptor (docking site) for these chemokines did not recruit CD8+ T cells and did not have an anti-tumour benefit.

“Humans whose tumors have higher levels of CD8+ T cells tend to have a better prognosis, respond better to treatment, and have reduced risk of cancer recurrence compared with patients whose tumors have lower levels of the immune cells, effects that were echoed by a reduced incidence of metastasis, or spread, of the cancers in mice that exercised,” said co-corresponding author, director of the Steele Labs at MGH, Dr. Rakesh K. Jain, and Professor of Radiation Oncology at HMS, Andrew Werk Cook.

CD8+ T cells are also essential for the success of drugs known as immune checkpoint inhibitors, such as Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab), which have revolutionised therapy for many types of cancer, but have to date had only limited success in breast cancer. The researchers found that exercise-trained mice displayed a much better response to immune checkpoint blockade, while the drugs did not work at all in sedentary mice.

“We showed that daily sessions of a moderate-to-vigorous intensity, continuous aerobic exercise training, lasting 30-45 minutes per session, induces a profound reprogramming of the tumor microenvironment that rewires tumor immunity, recruiting and activating CD8+ T cells to an unprecedented level with a non-pharmacological approach. Similar exercise training could be prescribed to a patient referred to an exercise oncology programme,” says Igor L. Gomes-Santos, PhD, lead author and exercise physiologist and post-doctoral fellow in the Steele Labs.

He notes that current clinical guidelines focus on general wellness, improved fitness levels and quality of life, but not necessarily on improved cancer treatment, especially immunotherapy, and that this lack of evidence limits its application in clinical practice.

More convincing, mechanism-based data are needed to motivate oncologists to discuss exercise training with their patients, to motivate patients to become more active and to expand implementation of outpatient exercise oncology programmes, the investigators say.

Meanwhile, in a recent Life Sciences study, researchers analyse the available scientific evidence supporting vitamin D as a neuro-protective agent against the neurological sequelae of coronavirus disease 2019 (COVID-19).

The infectious capacity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not limited to the respiratory system. In fact, SARS-CoV-2 can also invade other vital organs, including the central nervous system (CNS), which can result in several neurological consequences.

Some of the neurological manifestations of SARS-CoV-2 infection can include immune-mediated demyelinating disease, anxiety, stroke, depression, and neuro-degeneration. Two possible reasons why SARS-CoV-2 attacks the CNS include its ability to remain latent within cells for long periods, as well as its association with inducing the cytokine storm.

These neurological medical conditions can be worsened in COVID-19 patients with underlying chronic medical conditions such as hypertension, diabetes, or coronary heart diseases. As a result, this subset of COVID-19 patients is more likely to experience neurovascular sequelae of this disease.

There is considerable scientific evidence that vitamin D down-modulates the effects of neuro-inflammatory cytokines, thus weakening adverse consequences of COVID-19. Notably, vitamin D also has other anti-inflammatory/immune-modulatory effects.

In the current meta-analysis covering 54 independent studies examining the literature on COVID-19 and vitamin D, researchers found that patients with low 25-hydroxyvitamin D levels exhibited higher susceptibility to SARS-CoV-2 infection and related hospitalization. These patients were also at an increased risk of acute respiratory disease, hospital admission, and SARS-CoV-2-related mortality.

Due to the cytokine storm, some COVID-19 patients have reported acute necrotising hemorrhagic encephalopathy. During SARS-CoV-2 invasion of dendritic cells, monocytes, macrophages, and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1, and 6 (IL-1 and IL-6), are overexpressed.

Several studies have explored vitamin D and 25-hydroxyvitamin D3 (calcifediol) as novel therapeutic options for COVID-19-related neurological conditions. In fact, this type of supplementation has been shown to enhance innate immunity, such as early macrophage reaction to mucosal-invading viruses and bacteria, thereby reducing the incidence and severity of acute respiratory infections.

A sufficient plasma level of 25-hydroxyvitamin D converts into the hormone 1,25-dihydroxyvitamin D, which activates genes encoding antimicrobial substances against fungi, bacteria, and viruses, including SARS-CoV-2.

In their study, Durrant et al. showed that vitamin D3 supplementation efficiently induced gene expression associated with type I and type II IFN activity, which is critical to the innate response to bacterial and viral infections. Similarly, 1,25(OH)2D contributes to inhibiting the action of renin by increasing hACE2 production, while also reducing the cellular immune response induced by the cytokine storm during SARS-CoV-2-induced pneumonia.

Several clinical studies are also in the process of evaluating the possible optimization of SARS-CoV-2 vaccine efficacy by vitamin D supplementation.

The researchers concluded: “Taken together, data from several studies support the use of vitamin D supplementation, as well as its role in improving disease prognosis and preventing fatal consequences.

“In the future, longitudinal studies should follow up with COVID-19 patients to gather the data needed to evaluate the diagnosis, prognosis, and treatment of COVID-19-related neurological sequelae. Meanwhile, studies should also monitor vitamin D supplementation in current COVID-19 patients and in those who have recovered from the disease.

“To conclude, vitamin D could be a valuable addition to the current therapeutic arsenal against COVID-19 neurological sequelae.”

Also, eating protein from a greater variety of sources may lower risk of high blood pressure.

In a study of nearly 12,200 adults in China, eating protein from a greater variety of sources was associated with a lower risk of developing high blood pressure. This suggests that consuming a balanced diet with a moderate amount of protein from diverse food sources may help prevent new-onset hypertension.

Eating a balanced diet including protein from a greater variety of sources may help adults lower the risk of developing high blood pressure, according to new research published last week in Hypertension, a peer-reviewed journal of the American Heart Association.

Nearly half of the U.S. population has hypertension, or high blood pressure — one of the leading contributors to cardiovascular disease. When left untreated, high blood pressure damages the circulatory system and is a significant contributing factor to heart attack, stroke and other health conditions.

“Nutrition may be an easily accessible and effective measure to fight against hypertension. Along with fat and carbohydrates, protein is one of the three basic macronutrients,” said study author Xianhui Qin, M.D., of the National Clinical Research Center for Kidney Disease at Nanfang Hospital, Southern Medical University in Guangzhou, China.

There is a strong association between poor diet quality and increased risk of cardiovascular disease and death from cardiovascular disease. In its 2021 dietary guidance to improve cardiovascular health, the American Heart Association advises people eat healthy sources of protein, mostly from plants and may include seafood and low-fat or fat-free dairy products, and, if desired, lean cuts and unprocessed forms of meat or poultry. The American Heart Association recommends eating one to two servings, or 5.5 ounces, of protein daily.

The study authors analysed health information for nearly 12,200 adults living in China who were part of at least two out of seven rounds of the China Health and Nutrition Survey from 1997 to 2015 (surveys taken every two-four years). Participants’ initial survey was used as a baseline, while data from their last round was used as a follow-up for comparison. Participants were an average age of 41 years, and 47 per cent were men. The survey measured dietary intake in three consecutive 24-hour dietary recalls and a household food inventory. A trained interviewer collected 24-hour dietary information over 3 days in the same week during each round of the survey.

Participants were given a protein “variety score” based on the number of different sources of protein eaten out of eight reported: whole grains, refined grains, processed red meat, unprocessed red meat, poultry, fish, egg and legumes. One point was given for each source of protein, with a maximum variety score of 8. The researchers then evaluated the association for new onset hypertension in relation to the protein variety score.

New-onset hypertension was defined as systolic (top number) blood pressure greater than or equal to 140 mm Hg and/or diastolic (bottom number) blood pressure greater than or equal to 90 mm Hg, taking blood pressure-lowering medicine, or self-reporting that a physician diagnosed high blood pressure since their last survey visit. Average time to follow-up was six years.

The analysis found: More than 35 per cent of the nearly 12,200 participants developed new-onset high hypertension during follow-up.

Compared to participants with the lowest variety score for protein intake (less than two), those with the highest variety score (four or higher) had a 66 per cent lower risk of developing high blood pressure.

For each of the eight protein types, there was a window of consumption amount where the risk of hypertension was lower. Researchers described this as the appropriate level of consumption.

When total quantity of protein intake was considered, the amount consumed was divided into five categories (quintiles), from least to most intakes. People who ate the least amount of total protein and those who ate most protein had the highest risk for new onset of hypertension.

“The heart health message is that consuming a balanced diet with proteins from various different sources, rather than focusing on a single source of dietary protein, may help to prevent the development of high blood pressure,” Qin said.

A limitation of the study is its observational design. Because researchers used prior health information, they could not definitively prove protein intake of any kind or quantity caused or prevented new-onset hypertension.

Also, a pill made from the leaves of olive trees may act as a natural painkiller for some people, a study suggests.

Patients with severe knee joint pain who took the supplement twice a day for six months reported fewer aches compared to a placebo group.

The clinical trial did not find any improvement in people who were in moderate or low pain, however.

The Swiss researchers who led the study say olive leaf extract could provide an alternative to traditional pain meds, which can cause side effects after prolonged use.

The thin, flat leaves of olive trees contain high levels of compounds called polyphenols, which are known to have an anti-inflammatory effect.

Inflammation is one of the biggest factors in patients with chronic joint pain.

Studies have shown olive oil can protect the heart by reducing the build-up of fatty deposits inside the coronary arteries.

Olives have also been credited with helping to lower the risk of breast cancer, ulcerative colitis and even depression.

What is osteoarthritis? Osteoarthritis – sometimes called “wear and tear” – is a condition that occurs when the surfaces within joints become damaged. Cartilage covering the ends of bones gradually thin over time, and the bone thickens, according to Versus Arthritis.

Around a third of people aged 45 years and over in the United Kingdom (UK) suffer from the condition. This equates to roughly 8.75 million people. At least 20 million are known to suffer in the United States (US).

It is different to rheumatoid arthritis, a long-term illness in which the immune system causes the body to attack itself, causing painful, swollen and stiff joints.

Replacement joints are often necessary for osteoarthritis patients, because the joint has been worn down and causes agonising pain.

The study, published in the Therapeutic Advances in Musculoskeletal Disease journal, looked at 124 people aged 55 and over. It was led by Marie-Noëlle Horcajada, a Swiss bone scientist at food and drink giant Nestle — which funded the research.

Participants were split evenly between men and women and just over half were overweight. Exactly 62 people were given 125mg of olive leaf extract in tablet form twice a day.

The other half of participants received a placebo. Over six months, the participants completed a survey to assess their pain levels, known as the overall Knee injury and Osteoarthritis Outcome Score (KOOS) score.

They found the difference in KOOS — where higher scores indicate less pain and better mobility — was not significant between the placebo and supplement groups.

Those taking the supplement had a KOOS score of around 65 after six months, while the placebo group had scores of around 60.

But the extract was found to have a significant effect on people who had the highest pain levels to begin with.

In this group, KOOS scores were around 65 in the supplement group, compared to 50 in the placebo group.

Writing in the paper, the researchers said: “The dietary supplement may improve joint functional capacity in older people with high knee joint pain.

“Considering the adverse effects of anti-inflammatories and pain-killers, OLE could be of value as an alternative to these drugs in pain management of active subjects.”

Olive leaves have been used in natural medicine since the ancient Greece, who used it to boost their immune systems.

Also, scientists from the Bioreactors Research Group (BIO-110) of the University of Granada (UGR) have demonstrated that a natural treatment based on flour made from the insect Tenebrio molitor (more commonly known as the mealworm) can help prevent Type II diabetes mellitus.

The researchers successfully obtained and identified peptides (molecules comprising one or more amino acids linked by chemical bonds) that can exert a preventive effect against diabetes from the protein fraction of the insect Tenebrio molitor.

The study was published in the journal Food & Function.

The substrate used was flour from the insect, which was donated by the Salamanca-based company Tebrio, a pioneering company in the breeding of insects on an industrial scale in Europe. Insect production is more sustainable and economical than other means of obtaining protein sources and the nutritional value of this source is of interest for its use in human foodstuffs.

Type II diabetes mellitus is one of the most prevalent diseases in the world today, with more than 400 million people affected. The World Health Organisation estimates that it was the seventh most-prevalent cause of death in 2016 and that 700 million people may affect by this disease by 2045. The solutions currently applied in its treatment are insulin injections or the oral administration of various drugs that act by inhibiting enzymes such as DPP-IV or glucosidase, or hormone analogues involved in the restoration of insulin activity—a defining characteristic of this disease. However, these options often produce unwanted side effects in humans.

The potential use of peptides derived from dietary proteins with the ability to inhibit these enzymes, thereby generating an anti-diabetic effect in the patient, is now being actively investigated. Its advantage over current treatments is the absence of side effects and the relative ease with which these peptides can be obtained using natural protein resources. There are in vivo studies with milk and marine proteins, for example that show them to be a feasible alternative for use as active ingredients in functional food.

The study carried out at the UGR focused on obtaining peptides with an anti-diabetic capacity and involved optimizing the release of peptides contained in the protein of Tenebrio molitor by means of enzymatic processes. The scientists successfully obtained insect protein hydrolysates with bioactivity values comparable to traditional sources, pointing to the possibility of encouraging the production of this type of product from this sustainable protein source. Seven inhibitor peptides of the DPP-IV enzyme were identified, with a mean length of five amino acids, and six inhibitor peptides of the glucosidase enzyme, with a mean length of between two and four amino acids.

“The use of insects in functional food is—and will continue to be—a highly-relevant research topic as it offers a potential solution to various challenges that we currently face in society,” conclude the UGR researchers.