Lymph Node Organoids Integrate into the Lymphatic System and Restore Function

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The lymphatic system is vital to the correct operation of the immune response: lymph nodes are where immune cells communicate with one another in order to direct the response to invading pathogens and other threats. Unfortunately lymph nodes deteriorate with age, becoming inflammatory and fibrotic, no longer able to host the necessary passage and communication of immune cells. Researchers have demonstrated that, at least in late life, this can prevent improvements elsewhere in the aged immune system from producing the expected benefits in the immune response. What use extra immune cells or better immune cells if those cells cannot coordinate correctly? There are signs that lymph node degeneration may be due in part to the presence of senescent cells, in which case we might hope that senolytic therapies will help, but this has yet to be assessed by the research community.

What if new lymph nodes can be provided, however? Today’s open access paper is a report on the generation and transplantation of organoids capable of functioning as lymph nodes. In mice, transplanted organoids can integrate with the lymphatic system and begin to perform the duties of lymph nodes. While these were not aged mice, and the transplanted organoids replaced lymph nodes that had been surgically removed, rather than augmenting those damaged by aging, this is still promising. This line of research could become one of the suite of approaches that will needed to restore the immune system of an older individual to full, youthful function.

The other necessary therapies for immune rejuvenation are: regrowth of the thymus, responsible for maturation of T cells of the adaptive immune system, and which atrophies with age; rejuvenation of the hematopoietic stem cell population in the bone marrow, source of all immune cells, and damaged and diminished in older individuals; and clearance of the senescent, exhausted, misconfigured, and otherwise broken or inappropriate immune cells that come to clutter up the immune system in late life. A few different approaches for each of these line items are at various stages of development. Given a the timescale of a decade or two we should be optimistic that the effects of aging on the immune system can be significantly reversed.

Therapeutic Regeneration of Lymphatic and Immune Cell Functions upon Lympho-organoid Transplantation

Lymph node (LN) development is a multistep process involving crosstalk of multiple cell types and culminating in integration of LNs into the lymphatic system. Non-hematopoietic stromal progenitors of lymphoid organs play critical roles in tissue development, organization, and function through the secretion of cytokines, chemokines, and the extracellular matrix (ECM), a tri-dimensional scaffold that provides structural support and anchorage for cells. Afferent-collecting lymphatics transport lymph and antigens to the LN where immune responses are generated. However, surgical resection of LNs, radiation therapy, or infections may damage the lymphatic vasculature and contribute to secondary lymphedema, a chronic disease characterized by excessive tissue swelling, fibrosis, and decreased immune responses.

Currently available lymphedema treatments are limited to manual lymph drainage and compression garments, and definitive therapeutic options are still lacking. Vascularized autologous lymph node transfer (ALNT), a surgical procedure in which a LN flap is harvested and transplanted at the site of resected LNs to improve lymphatic drainage, is emerging as a therapeutic option for the treatment of cancer-associated lymphedema. Although feasible, such an approach requires surgical intervention and can be associated with donor-site complications, which may limit its application.

To circumvent these problems, tissue engineering may provide strategies to develop artificial lymphoid tissues for applications in regenerative medicine. It has been demonstrated that transplantation under the kidney capsule of an engineered stromal cell line expressing lymphotoxin α in a biocompatible scaffold or the delivery of stromal-derived chemokines in hydrogel is sufficient to promote the organization of lymphoid-like structures with immunological function. Whether these approaches contribute to regenerate immune and lymphatic functions in preclinical models of LN resection remains unknown.

Here, we generated lympho-organoids (LOs) using LN stromal progenitors in an ECM-based scaffold and show that LO transplantation at the site of resected LN contributes to restoration of lymphatic and immune functions. Upon transplantation, LOs are integrated into the endogenous lymphatic vasculature and efficiently restore lymphatic drainage and perfusion. Notably, upon immunization, LOs support the activation of antigen-specific immune responses and acquire properties of native lymphoid tissues. These findings provide a robust preclinical approach for the development of synthetic LOs capable of regenerating lymphatic and immune functions.

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How to reduce indoor air pollution

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Indoor air quality refers to the quality of air within the buildings and structures where you live. Understanding how to control common pollutants may help reduce your risk of immediate and long-term health effects. The American Lung Association1 maintains a list of common pollutants with a negative effect on your health, including building and paint products, carpets, formaldehyde, radon and volatile organic compounds (VOCs).

Indoor air pollution is one of the world’s largest environmental problems. According to the State of Global Air 2019 report,2 indoor air pollution could, on average, shorten the life of a person born in 2019 by 20 months. It may be responsible for more deaths than many other risk factors, such as malnutrition, physical inactivity and excessive alcohol use.

Long-term exposure contributes to nearly 5 million deaths related to stroke, heart attack and many other chronic diseases. The State of Global Air report 20193 suggests China’s efforts to fight air pollution are showing the first signs of progress, even as South Asia continues to lead the world as the most polluted region.

Unfortunately, air pollutants may be 100 times more concentrated inside than they are outside.4 As you are dependent on the quality of the air you breathe to support your respiratory system and overall health, paying attention to your indoor air quality is one step in helping you maintain optimal health.

According to the Environmental Protection Agency (EPA),5 poor indoor air quality is one of the top public health risks you face each day. Understanding and controlling indoor air pollution by making small changes to your living space may help reduce your overall health risks.

Plants don’t have a large impact on indoor air quality

While past research has demonstrated indoor plants help to filter some pollutants from indoor air,6 including an often-quoted study from NASA,7 other research suggests that while plants offer other health benefits, they may not be as effective at cleaning the air as was once thought.8

Luz Claudio,9 researcher and tenured professor at the Icahn School of Medicine at Mount Sinai in New York, reviewed much of the current and past research10 finding there was no question plants were capable of removing VOCs and toxins from the air under laboratory conditions.

However, in the real world, incorporating a few plants may not purify the air and there isn’t much hard science to back it up. Most of the studies used indoor plants in sealed environments but did not extend the studies to functional ways in which they might be used in the home.11

Stanley Kays, Professor Emeritus of horticulture at the University of Georgia co-wrote a study12 on the ability of 28 ornamental plants commonly used for interior plantings to remove volatile indoor pollutants, including benzene and toluene. The plants were purchased from commercial sources, the roots washed and the plants repotted.

Testing was done under laboratory conditions in which the plants were placed in gas-tight glass jars and the gases introduced. Of the 28 species tested, four had superior removal efficiencies for each of the tested compounds. Those plants were:13

  • Hemigraphis alternata (red-flame ivy or waffle plant)
  • Hedera helix (English ivy or European ivy)
  • Hoya carnosa (porcelainflower or wax plant)
  • Asparagus densiflorus (asparagus fern or foxtail fern)

Indoor air may be more polluted than outdoor air

The Clean Air Act amendment was passed in 199014 and is the legal authority regarding air pollution control. The legislation modified current legal authority provided by an earlier Clean Air Act in 1963 and 1970.

The amendment also addressed acid rain and toxic pollutants affecting the ozone layer. To be compliant, massive decreases in gas emissions were mandated and three major chemical contributors to the depletion of the ozone layer were phased out of use.15 The New Yorker reports16 that since the 1970s, emissions of many gases have fallen by 50% and particulate counts by 80%.

While this is a significant victory, the reality is most Americans spend 90% of their lives indoors.17 Unfortunately, those who are more susceptible to the adverse effects of air pollution, such as the elderly, those with cardiovascular or respiratory diseases or the young, will tend to spend even more time inside.

In recent decades, energy-efficient building construction has reduced mechanical ventilation and adequate air exchange, increasing the concentration of gases that may be found in buildings.18 Additionally, builders are increasing their use of synthetic materials and homeowners are furnishing their home with carpeting, personal care products and materials that off-gas toxic fumes.

Household cleaners, paint and glue products and even your electronic devices all contribute to poor indoor air quality. Less frequently, outdoor air pollutants may enter a building and contribute to poor air quality, such as harmful smoke from chimneys and volatile compounds from combustion engines.19 However, unlike outdoor air, indoor air quality is largely unregulated.

Cooking and cleaning impacts your indoor air quality

It wasn’t until after 9/11 that indoor air research attracted funding. One program began supporting research into HVAC filtration systems in an effort to detect traces of biological weapons. Biochemist Paula Olsiewski understood a complete lack of knowledge of baseline conditions inside a building would place first responders and others in a difficult position if they were unable to detect biological threat.20

With so few specialists in the area, she developed a team of 20 research groups from 13 universities and launched HOMEChem (House Observations of Microbial and Environmental Chemistry). The HOMEChem experiment took place in June 2018, during which the researchers attempted to identify the most crucial aspects of pollutants controlling the indoor environment.21

The test house was a 1,200 square-foot prefab home that had been on the University of Texas campus since 2006. The scientists devised a schedule to mimic real-life activities, including cleaning, cooking and simply hanging out. These became a series of controlled experiments during which they used state-of-the-art instruments to measure air quality.

Early in the experiment they found the instruments, which had been designed for outdoor measurements, had to be recalibrated to measure the higher concentrations building up inside. The data revealed cooking, cleaning and simply existing created emissions within the home.22

Researchers are now struggling with the question of how outdoor air pollution, long linked to negative health effects, may decrease life quality and expectancy when the majority of people do not spend much time outside. Several theories have been put forward and researchers are continuing to evaluate data and design studies to hopefully identify these links.

Katharine Hammond, an exposure scientist at UC Berkeley School of Public Health, commented on the results of the study,23 “The point of an experiment like this is that you start raising questions and figuring out how to go further into the detail.”

Health challenges associated with indoor air pollution

The impact of indoor air pollution is significant and may not yet be fully appreciated. Researchers are finding you don’t have to be sick to experience the impact from polluted air, including short-term respiratory irritation or breathing difficulties. The adverse effects on your health will depend on the type of pollutant, concentration and the length of your exposure.24

During high air pollution days, whether indoors or out, you may experience aggravation of any current cardiovascular or respiratory illness and an added stress to your heart and lungs. Long-term exposure to polluted air may permanently accelerate aging in your lungs and reduce your lung capacity, as well as exacerbate or trigger the development of illnesses such as asthma, emphysema and bronchitis.

Those who are most susceptible have a past medical history that includes heart diseases, asthma, emphysema or obstructive pulmonary disease. Pregnant women, older adults and children under 14 are also at higher risk. In 2013, the World Health Organization25 classified outdoor air pollution as carcinogenic to humans. As researchers learn more, can the classification of indoor pollution be far behind?

The Environmental Defense Fund26 reports air pollution is responsible for 6.4 million deaths each year, of which 600,000 are children. Evidence also suggests air pollution is associated with an increased risk of dementia,27,28 diabetes29 and autism.30,31

Health advantages to keeping plants

Although the benefits of reducing indoor air pollution may be less significant than previously thought, keeping plants indoors does have other benefits. You don’t need to be a psychologist to understand living plants look attractive. However, you’ll enjoy even more by having plants in your home.

According to a study published in the Journal of Physiological Anthropology,32 having active interaction with plants, such as smelling or touching them, may reduce psychological and physiological stress. While a walk in the park will accomplish the same thing, most spend a great deal of time indoors, so adding house plants may be beneficial.

Plants also act as a natural humidifier as they release moisture through their leaves. However, if you have children or pets, be sure the plants you bring home are safe. In one study,33 researchers found potted plants and flowers in your immediate work space may substantially improve your creativity and problem-solving skills and would improve concentration and boosted feelings of well-being by 47% at work.

Interaction with greenery and nature may also have a positive effect on your cardiovascular system and blood pressure,34 increase attentiveness,35 productivity,36 and raise job satisfaction.37

Tips to reduce your indoor air pollution

While the number of potential indoor pollutants is large, there are several things you can do to reduce the air pollution in your home and reduce your health risks.

Open the windows — One of the simplest and easiest ways to reduce the pollution count in your home is to open the windows and let a little fresh air in. Because most homes have little air leakage, opening your windows for as little as 15 minutes every day may improve the quality of the air you’re breathing.

Installing an attic fan is another way of bringing fresh air into the home and reducing your air conditioning costs. Install kitchen and bathroom fans that vent to the outside to remove contaminants from these rooms.38

Consider a heat recovery ventilator (HRV) — Since most newer homes are air-tight and therefore more energy efficient, air exchange with outdoor air is challenging. Some builders are now installing HRV systems to help prevent condensation and mold growth and improve indoor air quality.39

If you can’t afford an HRV, open your windows and run the bathroom and kitchen exhaust fans to vent your indoor air to the outside. You don’t have to do this for more than 15 to 20 minutes each day and should do it summer and winter at times when the temperature outside is closest to your indoor temperature. You might lose a little in electricity, but the improvement to your health is worth it.

Service fuel-burning appliances — Poorly maintained natural gas heaters and stoves, furnaces, hot water heaters, space heaters, water softeners and other fuel-burning appliances may leak carbon monoxide and nitrogen dioxide.40

Keep indoor humidity below 50% — Mold grows in damp and humid environments. Use a dehumidifier and air conditioner to keep your humidity under 50%. Keep the units cleaned so they aren’t a source of pollution.

Don’t smoke indoors — Ask smokers to go outside. Secondhand smoke from cigarettes, pipes and cigars contains over 200 known carcinogenic chemicals, endangering your health.

Don’t use scented candles, room fresheners or hazardous cleaning supplies — Candles and air fresheners release dangerous VOCs into your home. Instead, remove all garbage from your home as often as necessary and keep soiled laundry away from the living areas. Clean with less hazardous supplies, such as white vinegar and baking soda, and add essential oils for a clean scent.41

Test for radon — Radon is a colorless, odorless gas linked to lung cancer. It can be trapped under your home during construction and may leak into your air system over time. Radon testing kits are a quick and cheap way to determine if you are at risk.

Clean air ducts and change filters — The air ducts from your forced air heating and air conditioning units may be a source of pollution in your home. If there is mold growth, a buildup of dust and debris or if the ducts have become home to vermin, it’s time to call a professional and have them cleaned. Change your furnace filters every three months or earlier if they appear to be dirty.

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Ultraprocessed foods increase risk of death by 62%

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The National Institute of Diabetes and Digestive and Kidney Diseases defines overweight and obese as a person whose weight is higher than what is considered normal, adjusted for their height.1 That adjustment is figured by taking a person’s weight in kilograms and dividing it by the square of height in meters, which gives what is known as a body mass index, or BMI, according to the CDC.2

An adult is considered obese if their BMI is 30.0 or higher. Recent studies only reinforce what scientist and researchers already know: Obesity rates are high and climbing.

According to The State of Obesity,3 there are striking and persistent racial and ethnic disparities. According to data from the National Health and Nutrition Examination Survey in 2014, more than 33% of individuals were considered overweight.4

By 2016, that percentage had risen to 39.6%.5 The World Health Organization reported that worldwide, obesity has tripled since 19756 and in 2016 more than 1.9 billion adults were overweight. In the U.S., 39.6% of adults were overweight and 13% were obese. These are the highest rates ever documented.

The highest percentage of adults with obesity were from 40 to 59 years old and women 20 years and older.7 According to The State of Obesity,8 rates increased in six states between 2016 to 2017 and remained stable in the rest of the U.S. West Virginia had the highest adult obesity rate at 38.1% of the population, while obesity rates were at least 30% in 29 other states.

The American Academy of Family Physicians9 reported on the links found between increased obesity in adults and socioeconomic factors such as education, rural versus urban living and income levels. In all cases, the report showed individuals with the highest education, living in urban or metropolitan areas or with incomes 400% or greater than the federal poverty level had lower rates of obesity.

Two recent studies10,11 published in the BMJ have linked eating ultraprocessed foods with a significant increase in the risk of death and cardiovascular disease. While you may suspect boxed foods or convenience store snacks are foods on the ultraprocessed list, you may be surprised to learn that many foods touted as healthy are also ultraprocessed.

Four servings of ultraprocessed food increase risk of death

Researchers sought to evaluate the association between an ultraprocessed diet and the risk of all-cause mortality. To that end, they gathered data from 19,899 participants from 1999 to 2014.12 They followed up with the participants every two years to gather data on food and drink consumption and classified the foods eaten according to the degree of processing, using the NOVA classification system.13

NOVA classifies food categories according to the extent and purpose of processing, rather than in terms of nutrients found in the food. NOVA is recognized as a valid tool for nutrition and public health research and used in reports from the United Nations and Pan American Health Organization.14

NOVA categorization was initiated when researchers realized the significance of industrial processing on human health was far understated in research. The researcher’s main outcome measurement was an association between ultraprocessed foods and all-cause mortality.

Participants were categorized into eating low, low-medium, medium-high or high consumption of ultra-processed foods. The researchers found those in the highest quarter, eating greater than four servings of ultraprocessed food each day, had the greatest risk for all-cause mortality compared to those in the lowest quarter.15

During the 15-year study, 335 deaths occurred. For every additional serving of ultraprocessed foods, all-cause mortality-related increased by 18%. They concluded eating four or more servings of ultraprocessed foods was independently associated with a 62% relative increased risk for all-cause mortality.16

They also found those in the group with highest consumption had higher than average body mass index, were more likely to be current smokers and to have a family history of cardiovascular disease, diabetes and depression. In addition, they were also more likely to snack and use a computer for longer periods of time. The main cause of death was cancer at a mean age of 58 years.

Cardiovascular risk increases with ultraprocessed foods

Another recent study involved 105,159 participants. The researchers collected data on their dietary intake using repeated 24-hour dietary records designed to evaluate the participants’ typical eating habits. Here, their main outcome measurement was the risk of cardiovascular and cerebrovascular diseases.17

The mean follow-up of the participants was 5.2 years, during which the researchers found intake of ultraprocessed food was indeed associated with a higher risk of cardiovascular disease.

According to the researchers, the results remain statistically significant after adjusting for markers of nutritional quality and after a large range of sensitivity analysis. Co-author Maira Bes-Rastrollo, professor of preventive medicine and public health at the Universidad de Navarra, told CNN:18

“Ultraprocessed foods already make up more than half of the total dietary energy consumed in high-income countries such as USA, Canada and the UK. In the case of Spain, consumption of ultraprocessed food almost tripled between 1990 and 2010.”

Ultraprocessed food leads to weight gain

Another small scale, but rigorous, randomized and carefully controlled study19 performed by the National Institutes of Health (NIH), found that eating ultraprocessed foods increases calorie intake and leads to greater weight gain. The researchers recruited 20 healthy volunteers who lived at the NIH Clinical Center for four consecutive weeks.

They were randomized into two groups and received an ultraprocessed or unprocessed diet for the first two weeks and then immediately switched to the alternate diet for the next two weeks. After gathering the data, the researchers concluded that when eating a processed diet, the participants ate on average 459 more calories per day than when eating the unprocessed diet.20

The increased energy intake occurred over breakfast and lunch, with no significant increase in calories at dinner in those eating the ultraprocessed diet. The researchers also found that eating ultraprocessed meals caused the participants to eat faster, which may have led to a higher energy intake.

They hypothesized ultraprocessed foods may have increased the eating rate and delayed satiety signaling, thus increasing overall count caloric intake. While on the ultraprocessed diet for two weeks, participants gained an average of 1.98 pounds.21

Top cause of death linked to ultraprocessed foods: Cancer

According to the Centers for Disease Control and Prevention,22 there were 1.29 million new cancer cases reported in 1999 and 1.63 million new cancer cases reported in 2015. According to the American Cancer Society,23 there were an estimated 14.1 million cases of cancer diagnosed around the world in 2012 and the number is estimated to grow to 21.6 million by 2030.

The established dogma asserting cancer is a genetic disease currently influences research and the type of treatment you may expect from an oncologist. In fact, it fuels the entire cancer industry, but it is not leading to any significant advances in treatment or prevention.

However, the mechanism of metabolism on cancer cells is clear and based on the findings of Dr. Otto Warburg, a classically trained biochemist who received the Nobel Prize in Physiology or Medicine24 in 1931 for his discovery of the nature and action of the respiratory enzyme cytochrome C oxidase.

His work demonstrated how cells receive energy from respiration and how cancer cells have a fundamentally different energy metabolism compared to a healthy cell. The National Cancer Institute25 reports tobacco is the current leading cause of cancer and the leading cause of death from cancer.

Although smoking has been in the No.1 spot for preventable causes of cancer for decades, it appears obesity is not far behind. According to Dr. Otis Brawley,26 professor of oncology in epidemiology at Johns Hopkins University and past chief medical officer of the American Cancer Society, this may occur within the next five or 10 years.27

Compared to those who are within a normal weight range, those who are obese are also more likely to have a recurrence of their cancer, and a lower likelihood of survival. Research published in the New England Journal of Medicine28 concluded “increased body weight was associated with increased death rates for all cancers combined and for cancers in multiple specific sites.”

Reuters29 reports the rate of cancer unrelated to obesity declined by 13% between 2005 and 2014 while obesity-related cancers rose by 7%. While the exact association between cancer and obesity is not fully understood, researchers are focusing on studying visceral fat, as its metabolically active and may spur cellular growth.

Obesity increases risk of other health concerns

In addition to cancer, obesity eventually takes a toll on your physical and financial health, even if you are currently healthy. Adults who are obese spend 42% more on direct care costs and those who are morbidly obese (BMI greater than 40) pay 81% more than a healthy weight adult.30

When a patient presents in the emergency room with chest pain, the cost is 41% higher for severely obese patients, 28% higher for obese patients and 22% higher for overweight patients than healthy weight individuals.31 Additional financial costs are the result of medical and physical concerns linked with obesity, such as Type 2 diabetes, cardiovascular disease and gallstones.

During Type 2 diabetes, the body struggles to maintain healthy levels of blood sugar due to insulin resistance. The hormone insulin is produced by your pancreas and helps keep your blood sugar levels within a normal range. If you experience Type 2 diabetes, your pancreas may not be able to produce enough insulin to keep up with the demand, resulting in higher blood sugar levels.32

Obesity33 and Type 2 diabetes34 both drastically increase your risk for coronary heart disease. A buildup of plaque in the arteries severely limits the flow of blood to the heart and a heart attack may happen. Obesity may also increase your risk for high blood pressure, which can increase your heart’s workload to the point of arterial damage and heart damage.

Gallstones35 are a crystal-like deposit created inside the gallbladder typically made from an excess of cholesterol, bile or bilirubin. In the case of obesity, the stones are usually made from cholesterol, and the size may vary from a grain of sand to the size of a golf ball.36

Unless they cause a blockage in the pancreatic duct, they don’t usually trigger symptoms. Obesity may also limit your physical activity and increase your risk for osteoarthritis in your knees, back and hips.

What’s in ultraprocessed foods?

According to NOVA, the ultraprocessed group of food and drinks contains industrial formulations, typically with five or more of these types of ingredients. They may include sugar, oils, fats, preservatives and antioxidants not commonly found in culinary preparations but may be used to imitate sensory qualities or hide undesirable sensory qualities.37

While this list is not all-inclusive, it does offer insight into the types of foods considered ultraprocessed:38

Ice cream



Mass-produced bread and buns

Margarines and spreads

Powdered or packaged instant soups, noodles and desserts


Cakes and cake mixes

Breakfast cereals


Energy bars

Energy drinks

Fruit yogurt

Fruit drinks

Cocoa drinks

Instant sauces

Infant formulas

Ready-to-heat products

Your diet is a key factor in health and longevity

Undoubtedly, there is a serious health epidemic in the U.S., and a majority of it is linked to diet. There are no quick and easy answers. It is crucial to remember what you eat is the foundation on which your health is built and eating a processed food diet is a recipe for long-term disaster.

If you have access to real food, it is important to take the time to learn to cook from scratch and make the most of any leftovers. With a bit of dedication and planning it’s also possible to grow produce at home in small spaces, including indoors.

Eating a diet of 90% real food and 10% or less processed foods is achievable and may make a significant difference in weight management and overall health. For a list of guidelines to help you get started, see my previous article, “Why a Calorie Is Not a Calorie.”

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Cellular Antioxidant Defenses Measured in Blood Samples Decline with Age

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Cells are in a constant state of generating oxidative molecules, clearing those molecules via the use of antioxidant proteins, and repairing the damage caused by oxidative reactions. Researchers here show that aging is accompanied by declining amounts of the natural antioxidants involved in clearing oxidizing molecules from cells, preventing them from reacting with cellular machinery to cause damage. This is an unfortunate downstream consequence of the underlying causes of aging, one that will cause further dysfunction in cells. Exactly how and why this is a feature of aging, the exact chain of cause and effect that leads from the underlying damage to this result, remains to be determined. At the present time, the fastest approach to answering that sort of inquiry is likely to build rejuvenation biotechnologies that can repair specific forms of molecular damage thought to cause aging, and then see what happens when the therapies are applied in animal studies.

An integral part of aerobic metabolism is reactive oxygen species (ROS) generation which should be analyzed according to its two main functions. On the one hand, ROS plays an important role in biomodulating and regulating many cellular functions, such as defense against pathogens, signal transduction processes during transmission of intercellular information, and activation of specific transcription factors. On the other hand, an excessive quantity of ROS has a deleterious effect on cells, reacting with a variety of molecules and thereby interfering with cellular functions. To cope with the elevated generation of ROS, ROS-scavenging biochemical pathways have been developed in aerobic cells.

In recent years there have been a lot of studies supporting the role of ROS in molecular aging mechanisms. The confirmation of oxidative stress increase with age of diverse organisms, and the generation of transgenic invertebrates overexpressing the antioxidant enzymes with increased lifespan were among the most important results of these studies. Nevertheless, there were no alterations in the lifespan in most of the examined mouse models, which under- or overexpressed a wide variety of genes coding for antioxidant enzymes. Thus, the role of oxidative stress in aging mammals is not fully understood and still demands further inquiries.

In this study, analysis of antioxidant defense was performed on the blood samples from 184 “aged” individuals aged 65-90+ years, and compared to the blood samples of 37 individuals just about at the beginning of aging, aged 55-59 years. Statistically significant decreases of Zn,Cu-superoxide dismutase (SOD-1), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were observed in elderly people in comparison with the control group. Moreover, an inverse correlation between the activities of SOD-1, CAT, and GSH-Px and the age of the examined persons was found. No age-related changes in glutathione reductase activities and malondialdehyde concentrations were observed. These lower activities of fundamental antioxidant enzymes indicate the impairment of antioxidant defense in the erythrocytes of elderly people.


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Extremely Long Lived Cells are Found in Many Tissues, Not Just the Brain

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Researchers here report that the brain is not the only organ to exhibit cells that are as long-lived as the animal containing them. A number of other organs contain at least some long-lived cells, even for tissues thought to be highly regenerative and in which tissue turnover is comparatively rapid, such as the liver. It remains to be seen as to how this new information interacts with present thinking on the damage of aging, in which there is a central role for a reduction in stem cell activity and consequent loss of new cells generated to replace old tissue populations.

Scientists once thought that neurons, or possibly heart cells, were the oldest cells in the body. Now, researchers have discovered that the mouse brain, liver, and pancreas contain populations of cells and proteins with extremely long lifespans – some as old as neurons. “We were quite surprised to find cellular structures that are essentially as old as the organism they reside in. This suggests even greater cellular complexity than we previously imagined and has intriguing implications for how we think about the aging of organs, such as the brain, heart, and pancreas.”

Since the researchers knew that most neurons are not replaced during the lifespan, they used them as an “age baseline” to compare other non-dividing cells. The team combined electron isotope labeling with a hybrid imaging method (MIMS-EM) to visualize and quantify cell and protein age and turnover in the brain, pancreas and liver in young and old rodent models. To validate their method, the scientists first determined the age of the neurons, and found that – as suspected – they were as old as the organism. Yet, surprisingly, the cells that line blood vessels, called endothelial cells, were also as old as neurons. This means that some non-neuronal cells do not replicate or replace themselves throughout the lifespan.

The pancreas, an organ responsible for maintaining blood sugar levels and secreting digestive enzymes, also showed cells of varying ages. A small portion of the pancreas, known as the islets of Langerhans, appeared to the researchers as a puzzle of interconnected young and old cells. Some beta cells, which release insulin, replicated throughout the lifetime and were relatively young, while some did not divide and were long-lived, similar to neurons. Yet another type of cell, called delta cells, did not divide at all. The pancreas was a striking example of age mosaicism, i.e., a population of identical cells that are distinguished by their lifespans.

Prior studies have suggested that the liver has the capacity to regenerate during adulthood, so the researchers selected this organ expecting to observe relatively young liver cells. To their surprise, the vast majority of liver cells in healthy adult mice were found to be as old as the animal, while cells that line blood vessels, and stellate-like cells, another liver cell type, were much shorter lived. Thus, unexpectedly, the liver also demonstrated age mosaicism.


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Progerin Acts in Normal Aging as well as Progeria, but is it Important?

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Hutchinson-Gilford Progeria Syndrome, or just progeria, results from the production of a broken protein progerin from the Lamin A gene. The functional form of Lamin A is vital to the structure of cells, and without it cellular damage and tissue dysfunction rapidly accrue. This results in a short lifespan with a superficial resemblance to accelerated aging. It is not accelerated aging, however: aging is a specific mix of forms of cell tissue damage and consequent dysfunction, and progeria is a radically different mix. Where there are similar outcomes, it is because some tissues will tend to fail in similar ways regardless of the specific cause of underlying cellular dysfunction.

While progeria results from the rare occurrence of mutation in the Lamin A gene, in recent years the presence of progerin at low levels has been observed in old individuals undergoing normal aging. This appears to be associated with cellular senescence, with progerin production being, for reasons yet to be fully understood, a feature of senescent cells. Even in very late life only a small fraction of cells in any given tissue are senescent, accounting for the overall low level of progerin, but senescent cells inflict an outsized level of harm on tissue function via a potent inflammatory mix of secreted proteins.

When we ask whether progerin is important in natural aging, this may just boil down to whether or not it is doing anything beyond participating in some way in the biochemistry of senescent cells. If it is just another portion of the internal mechanisms of cellular senescence, then it will not be necessary to tackle it as a distinct mechanism. The dominant approach to senescent cells in aged tissue is to selectively destroy them: no more senescent cells, no more progerin. Alternatively, are normal cells in aged tissues falling into a state in which they produce enough progerin in order to become senescent? Even in this case we may still be able to ignore this mechanism for practical purposes, given efficient enough senolytic treatments to clear out senescent cells every so often.

Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?

The Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the protein lamin A – progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription.

Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone H2AX phosphorylation marks of the DNA damage loci. Inhibition of progerin production in cells of aged non-HGPS donors in vivo increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, IGFBP3, and GADD45B to the levels of young donor cells. Thus, progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS.

Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GHIGF1, MAPK, TGFβ, and mitochondrial dysfunction. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. It may be suggested that these systems translate the effects of various internal and external factors into universal molecular hallmarks, largely common between natural and accelerated forms of aging.

Drugs acting at both natural aging and HGPS are likely to exist. For example, vitamin D3 reduces the progerin production and alleviates most HGPS features, and also slows down epigenetic aging in overweight and obese non-HGPS individuals with suboptimal vitamin D status.

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Mast Cells in Age-Related Neurodegeneration and Neuroinflammation

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Of late, it is becoming clear that the dysfunction of immune cells of the central nervous system, such as microglia, is an important part of neurodegeneration. Growing degrees of cellular senescence in these cell populations, leading to inflammatory signaling, appears to be significant in the progression of Alzheimer’s disease, for example. There are many distinct types of supporting cell in the brain, however. This short open access review paper discusses the evidence for dysfunction of the immune cells known as mast cells to be relevant to the progression of chronic inflammation and neurodegeneration in the aging brain.

Mast cells are “first responders” that become activated with exposure to a diverse array of stimuli, from allergens and antigens to neuropeptides, trauma, and drugs. Activated mast cells are multifunctional effector cells that exert a variety of both immediate and delayed actions.

Neuroinflammation, which is now recognized as a primary pathological component of diseases such as multiple sclerosis, is gaining acceptance as an underlying component of most, if not all, neurodegenerative diseases. Whereas past focus has predominantly centered on glial cells of the central nervous system, recently mast cells have emerged as potential key players in both neuroinflammation and neurodegenerative diseases. Mast cells are well positioned for such a role owing to their ability to affect both their microenvironment and neighboring cells including T cells, astrocytes, microglia, and neurons. The secretory granules of mast cells contain an arsenal of preformed/stored immunomodulators, neuromodulators, proteases, amines, and growth factors that enable complex cross-communication, which can be both unidirectional and bidirectional. Mast cells can also affect disruption/permeabilization of the blood-brain barrier and this has the potential for dramatically altering the neuroinflammatory state.

With respect to Alzheimer’s disease (AD), Parkinson’s disease (PD), ALS, and Huntington’s disease (HD), mast cell perturbation of the blood-brain barrier appears to share a commonality. Moreover, mast cells have been found to home to sites of amyloid deposition in AD; and, an inhibitor of mast cell function was shown to reduce cognitive decline in AD patients. Mast cell interactions with neurons and glial cells have also been implicated in PD pathogenesis. Emerging evidence suggests that mast cell autocrine signaling may contribute to ALS: The mast cell chemoattractant, IL-15, is elevated in the serum and cerebrospinal fluid of ALS patients; and, mast cells expressing IL-17 have been found in the spinal cord of ALS patients. Plasma levels of cytokines (IL-6, IL-8), known to affect mast cell activation, have been correlated with functional scores in HD patients suggesting the possible involvement of mast cells in the pathogenesis of HD.


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A Natural Mechanism that Breaks Down α-Synuclein Aggregates

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The brain exhibits a range of natural mechanisms for the clearance of various protein aggregates involved in neurodegenerative disease, both inside and outside the cells: clearance via immune cells; autophagy within cells; carried away via drainage of cerebrospinal fluid; and so forth. Clearly these mechanisms falter and become overwhelmed with advancing age, an outcome that results from a progressively increased burden of cell and tissue damage. Where a natural repair and maintenance mechanism exists, looking for ways to enhance that mechanism is one of the logical places to make a start on the development of viable therapies.

Aggregates of the protein alpha-synuclein in the nerve cells of the brain play a key role in Parkinson’s and other neurodegenerative diseases. These protein clumps can travel from nerve cell to nerve cell, causing the disease to progress. Relevant for these diseases are long but yet microscopic fibres, or fibrils, to which large numbers of the alpha-synuclein molecules can aggregate. Individual, non-aggregated alpha-synuclein molecules, however, are key to the functioning of a healthy brain, as this protein plays a key role in the release of the neurotransmitter dopamine in nerve cell synapses.

When the protein aggregates into fibrils in a person’s nerve cells – before which it must first change its three-dimensional shape – it can no longer carry out its normal function. The fibrils are also toxic to the nerve cells. In turn, dopamine-producing cells die, leaving the brain undersupplied with dopamine, which leads to typical Parkinson’s clinical symptoms such as muscle tremors. “Once the fibrils enter a new cell, they ‘recruit’ other alpha-synuclein molecules there, which then change their shape and aggregate together. This is how the fibrils are thought to infect cells one by one and, over time, take over entire regions of the brain.”

Researchers were able to decipher a cellular mechanism that breaks down alpha-synuclein fibrils naturally. A protein complex called SCF detects the alpha-synuclein fibrils specifically and targets them to a known cellular breakdown mechanism. In this way, the spread of fibrils is blocked, as the researchers demonstrated in tests on mice: when the researchers switched off SCF’s function, the alpha-synuclein fibrils were no longer cleared up in the nerve cells. Instead, they accumulated in the cells and spread throughout the brain.

The more active the SCF complex, the more the alpha-synuclein fibrils are cleared, which could slow down or eventually stop the progression of such neurodegenerative diseases. The SCF complex is very short-lived, dissipating within minutes. Therapeutic approaches would focus on stabilising the complex and increasing its ability to interact with alpha-synuclein fibrils. For example, drugs could be developed for this purpose. “However, when it comes to potential therapies, we’re still right at the beginning. whether effective therapies can be developed is still unclear.”


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Could cranberries combat superbugs?

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Finding a drug to either kill harmful bacteria or slow their growth has been a priority for medical practitioners for thousands of years. Not all antibiotics have been effective or even safe, although herbs, honey and moldy bread poultices used in ancient Greece, Rome, China and Egypt were used with some success.1

Needless to say, as scientists experimented with treatment possibilities and resorted to things like animal feces, heavy metals like mercury, bismuth and arsenic to eradicate sexually transmitted diseases such as gonorrhea and syphilis via specially designed syringes, the “administration and side effects often proved worse than the disease.”2

The Journal of Antimicrobial Chemotherapy references many attempts over centuries to nail down a definitive antibiotic, and several showed great promise, such as Pyocyanase, derived from a green bacteria isolated from injured peoples’ bandages, which slowed the growth of other microbes. “They grew the organism (Pseudomonas aeruginosa) in batches and used the supernatant as a medicine, with mixed success.”3

Sulfa drugs such as a prominent one called Prontosil, first tested in 1935, also showed promise.4 At times, catastrophic illnesses made the search more desperate, as when an herb called qinghaosu (artemisinin) used for millennia in traditional Chinese medicine (TCM), was tried and found to be a potent treatment for malaria as late as the 1970s.5

But since the discovery of penicillin in 1929 and its mass production and distribution in 1945,6 not only the study of medicine has changed, but the world.

Frontiers in Microbiology suggests that antimicrobials could be called the most successful chemotherapy agents since the study of medicine began, noting, “It is not necessary to reiterate here how many lives they have saved and how significantly they have contributed to the control of infectious diseases.”7

‘Germs will always look for ways to survive’

However, overuse has created a dire situation: The successes have been “marred by the emergence of hard-to-treat multiple antibiotic-resistant infections.”8 In fact, as the U.S. Centers for Disease Control and Prevention observes, “Germs will always look for ways to survive and resist new drugs.”9

According to researchers at McGill University, antibiotic resistance is undermining decades of progress in fighting bacterial infections. Antibiotics are used not only in medicine but in agriculture. In fact, methicillin-resistant Staphylococcus aureus (MRSA) and other superbug infections have been spreading rapidly among people both inside and outside of hospital settings.10 McGill scientists asserted:

“We are on the cusp of returning to a pre-antibiotic era in which minor infections can once again become deadly. Therefore, countering the fall in antibiotic efficacy by improving the effectiveness of currently available antibiotics is a crucial goal.”11

But in May 2019, a familiar plant-based product was found to make bacteria more sensitive to antibiotics and prevent resistance. Testing the popular belief that cranberries, even more than the juice, might be effective agents against painful and often debilitating urinary tract infections (UTIs),12 the researchers wanted to see how its compounds would stand up against some of the most virulent strains.

Cranberries are tapped to help fight pathogenic bacteria

The journal Advanced Science13 reports that cranberries — or more specifically, the proanthocyanidins in cranberries — are very effective in the fight against pathogenic bacteria. EurekAlert explains results from the study:

“Countering the fall in antibiotic efficacy by improving the effectiveness of currently available antibiotics is a crucial goal … When treated with molecules derived from cranberries, pathogenic bacteria become more sensitive to lower doses of antibiotics. What’s more, the bacteria don’t develop resistance to the antibiotics.

Given the popular belief that drinking cranberry juice is helpful against urinary tract infections, the researchers sought to find out more about the berry’s molecular properties by treating various bacteria with a cranberry extract. The bacteria selected for study were those responsible for urinary tract infections, pneumonia, and gastro-enteritis (Proteus mirabilis, Pseudomonas aeruginosa, and Escherichia coli).”14

According to Nathalie Tufenkji, McGill chemical engineering professor and the study’s lead author, “Normally when we treat bacteria with an antibiotic in the lab, the bacteria eventually acquire resistance over time.” But when her team treated these bacteria with a combination of an antibiotic along with a cranberry extract, they were surprised to be able to report that “no resistance developed.”15

The researchers wrote that cranberry proanthocyanidins, which they called CPAC, prevent not only the “evolution of resistance” to tetracycline in Escherichia coli and Pseudomonas aeruginosa, but “rescues antibiotic efficacy” when posed against cells exposed to antibiotics and, further, inhibited biofilm formation.

Further study revealed the resistance happened two ways: First, the cranberry extract made the bacterial cell wall more permeable so the antibiotic could reach it, and second, it rendered the bacteria less able to get rid of it. As such, the antibiotic was more effective at lower doses. In addition:

“After confirming the activity of the cranberry molecules on bacterial culture, the researchers tested to determine whether the pattern persisted in a preliminary animal model: infected insects. Since the synergistic effect of the extract and the antibiotic was also observed in the insects, further experiments will be conducted to clearly identify the active molecules.”16

What are cranberries good for? Researchers weigh in

There’s been some controversy regarding the efficacy of cranberries for bladder infections, but increasingly, the positive research on cranberries begins to make more sense when you find how many diseases and disorders the small, tart red fruit can benefit. Here are a few important ones:

Cardiovascular disease — The impacts of cranberries on not just the cardiovascular system but every component of metabolic syndrome was explored in a 2017 review. It listed several areas impacted, including reduced obesity markers (body weight, body mass index and waist circumference), blood pressure and balanced blood sugar levels.17

Cancer — A 2016 review on what compounds in cranberries can do for cancer noted that 17 different types, including cancers of the colon, bladder, prostate, esophagus and stomach, as well as glioblastoma and lymphoma, were inhibited by cranberries or cranberry-derived constituents.

Cranberries may fight cancer, in part, due to apoptosis, necrosis and autophagy due to “reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways.”18

Oral health — Proanthocyanidins in cranberries may help prevent bacteria from binding to teeth and prevent gum disease, one study notes. “Clearly, cranberry (proanthocyanidins) show promise for the development of novel alternative or adjunctive anticaries chemotherapy.”19

Ironically, cranberry juice was a popular remedy recommended by doctors for many years for UTIs, but more recent research suggests that the placebo effect might have accounted for the successes the use of cranberry juice elicited more than solid science,20 especially since its active ingredient is likely “long gone before it reaches your bladder,”21 one researcher explains.

What problems can antibiotics cause?

Research in 201822 showed that, particularly for children, antibiotic use can cause short-term problems, but they also can trigger a permanent change in your gut microbiome, which accounts for nearly 80 percent of your immune system function, so it is important to use antibiotics only when absolutely necessary.

They’ve also been found to cause mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) in human cells, DNA and vital organs.23 But that doesn’t stop doctors from prescribing them — often unnecessarily. The CDC notes:

“In 2015 alone, approximately 269 million antibiotic prescriptions were dispensed from outpatient pharmacies in the United States, enough for five out of every six people to receive one antibiotic prescription each year. At least 30 percent of these antibiotic prescriptions were unnecessary.”24

As if that weren’t enough, besides ruptured tendons, kidney stones and/or failure, retinal detachment and blindness, and ruptured aorta (the main artery supplying oxygenated blood to your circulatory system), research emerged that antibiotics can also raise the risk of mental disorders, such as schizophrenia, autism and numerous personality and behavior disorders.25

Fluoroquinolones are a type of antibiotic often prescribed for upper respiratory and urinary tract infections. However, because of the damage they’ve been known to cause, from acute kidney failure to psychotic reactions to “fatal events,”26 antibiotics — and fluoroquinolones in particular — should be used only as a last resort.

More on the dangers of overusing antibiotics

The U.S. Food & Drug Administration (FDA) issued a warning in 2017 about an increased risk of ruptures or tears in the aorta due to the use of fluoroquinolones in certain patients.27 In 2018, the journal Nature mentioned the commonly prescribed drug causes “rare but disabling” side effects, noting that in 2015, doctors prescribed them 32 million times, making them the fourth-most popular antibiotic in the U.S. Further:

“Fluoroquinolones are valuable antibiotics, and safe for most people. Yet they are so widely prescribed that their side effects might have harmed hundreds of thousands of people in the United States alone, say scientists who are working with patients to unpick FQAD’s causes.

Fluoroquinolone toxicity, they say, provides a compelling example of an emerging understanding that antibiotics don’t just harm microbes — they can severely damage human cells, too.”28

Antibiotic use for two months or longer by women aged 60 and older has been shown to lead to a 32% increased risk of developing cardiovascular disease, including heart attack and stroke. It’s important to note the likely reason: Antibiotics have the power to not only alter your gut, but “wipe out” your microbiome.29 Interestingly, the study concludes:

“The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.”30

One of the best and least expensive ways to optimize your gut microbiome is to eat traditionally fermented and fiber-rich foods. But there’s also spore-based probiotics, aka sporebiotics, which make use of the microbe Bacillus to dramatically increase your immune tolerance.

If you must take antibiotics, I recommend taking the beneficial yeast Saccharomyces boulardii after you’ve finished to prevent secondary complications of antibiotic treatment, such as diarrhea.

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The crucial connection between magnesium and vitamin B6

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You may be familiar with the connection between magnesium, calcium and vitamins K2 and D, and how they work in tandem. But are you aware of the crucial link between magnesium and vitamin B6 (pyridoxine)? Individually, magnesium and vitamin B6 are both essential for heart and brain health. Both also play roles in the regulation of your blood sugar level.1,2

When you get insufficient amounts of magnesium from your diet, your body will leach magnesium from your bones, muscles and internal organs, which can lead to osteoporosis, kidney problems and liver damage.

Vitamin B6 can help ameliorate this by escorting magnesium to the cells that need it most, thus ensuring that the magnesium you’re getting, whether from foods or supplements, is being used as efficiently as possible. In so doing, vitamin B6 also helps augment the many benefits of magnesium.

Magnesium-B6 combo is superior for severe stress

The importance of magnesium in combination with vitamin B6 was presented in a 2018 study3 in the journal PLOS ONE. Taken together, these two nutrients have been shown to have a complementary effect on stress reduction in animal studies.

In this randomized trial, they evaluated whether the combination of magnesium and B6 would improve perceived stress levels in 264 human subjects who also had low magnesium to start. Healthy adults with a depression anxiety stress scale score above 18 and a serum level of magnesium between 0.45 nanomoles per liter (mmol/L) and 0.85 mmol/L were randomized to receive either:

  1. 300 milligrams (mg) of magnesium in combination with 30 mg of vitamin B6
  2. 300 mg of magnesium only

The primary endpoint was a reduction in stress score from baseline to Week 8. While both treatment groups experienced similar reductions in their stress scores — the magnesium-B6 combo group reporting a 44.9% reduction in perceived stress and the magnesium-only group a 42.4% reduction — a more significant impact was shown in those with severe and/or extremely severe stress.

According to the authors, adults with a stress score at or above 25 had a 24% greater improvement with magnesium-vitamin B6 versus magnesium only at Week 8. Those taking magnesium and B6 in combination also experienced fewer side effects: 12.1% of those taking magnesium-vitamin B6 versus 17.4% of those taking magnesium only experienced some form of adverse event. As noted by the authors:4

“These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.”

Magnesium and B6 may ease premenstrual syndrome

Magnesium and vitamin B6 are two nutrients commonly recommended for women struggling with premenstrual syndrome. According to a research paper5 published in the Journal of Caring Sciences, magnesium deficiency has been proposed “as one of the factors causing and intensifying premenstrual syndrome symptoms,” and magnesium appears to work because it has a calming effect on the neuromuscular system.

“Vitamin B6 is another proposed treatment for this syndrome,” the paper notes.6 “On the one hand vitamin B6 increases serotonin and dopamine levels and improves premenstrual syndrome symptoms, and on the other, it has an essential role in the synthesis of prostaglandin and fatty acids, which are reduced in etiologies causing premenstrual syndrome.

Moreover, researchers believe that vitamin B6 deficiency decreases dopamine in the kidneys and therefore increase sodium excretion, which in turn causes water accumulation in the body and induces symptoms such as swelling in extremities, edema, and abdominal and chest discomfort. The administration of vitamin B6 can thus decrease these symptoms and improve premenstrual acne.”

To evaluate the effects of these two nutrients on premenstrual syndrome, 126 women diagnosed with premenstrual syndrome, based on American Psychiatric Association criteria, were divided into three groups, which received either 250 mg of magnesium oxide, 250 mg of vitamin B6, or a placebo, taken from the first day of the menstrual cycle until the beginning of the next cycle.

Magnesium and B6 have similar rates of effectiveness

Overall, magnesium and B6 had similar rates of effectiveness for premenstrual syndrome in this Journal of Caring Sciences study. Mean scores of premenstrual syndrome before and after intervention in the three groups were as follows:

Magnesium Vitamin B6 Placebo

Before intervention: Before intervention

Magnesium : 36.89%

Vitamin B6 : 36.51%

Placebo : 35.8%

After intervention: After intervention

Magnesium : 22.22%

Vitamin B6 : 22.84%

Placebo : 28.41%

As you can see, while the placebo also helped reduce premenstrual syndrome symptoms, magnesium and B6 did so more effectively, and at similar rates. When looking at specific symptoms, B6 and magnesium were found to be the most effective for lowering rates of depression, water retention and anxiety. In conclusion, the authors noted:7

“Considering the importance of premenstrual syndrome and the numerous effects it has on society and the lives of women, health groups should prioritize the diagnosis and treatment of this syndrome. Since there is no definitive etiology and treatment for this syndrome, many researchers have tried to find the best and most effective drug with the least side effects to prevent the occurrence of the syndrome …

The current study was also undertaken with the goal of finding an effective compound with no side effects to reduce the symptoms of this syndrome and its direct and indirect economic and social effects. All compounds used in the current study had no side effects, were effective, non-chemical, and acceptable by most groups of women in the society.

Hence, health groups, especially midwives, can compare the effectiveness the compound on their specific patients and select the most appropriate treatment for each individual. Moreover, in cases where the patient is prohibited from using chemical drugs to treat premenstrual syndrome, such as oral contraceptive pills and gonadotropin releasing hormone (GnRH) agonists, the use of these compounds seems effective …”

Unfortunately, a combination of magnesium and B6 was not evaluated in this study. It would have been interesting to see what their combined effect would have been. Considering the importance of both of these nutrients for health, I see no risk in combining them, though, should you struggle with premenstrual syndrome.

The importance of magnesium for optimal health

Magnesium8 is the fourth most abundant mineral in your body and the second most common intracellular cation9 (positively charged ion) after potassium. It’s required for the healthy function of most cells in your body, but is especially important for your heart, kidneys and muscles.

Low magnesium will impede your cellular metabolic function and deteriorate mitochondrial function, which can have far-reaching health consequences, seeing how loss of mitochondrial function is a foundational factor in most chronic diseases, including heart disease and cancer.

According to one scientific review,10 which included studies dating as far back as 1937, low magnesium actually appears to be the greatest predictor of heart disease, and other recent research shows even subclinical magnesium deficiency can compromise your cardiovascular health.11

Being one of the most abundant minerals in the human body, it’s not surprising that it has several hundred biological functions. To list just a few, magnesium helps: 

  • Relax your muscles as well as your blood vessels — Being deficient in it can cause muscle cramps and weakness
  • Promote mental and physical relaxation — It’s a stress antidote that works by boosting GABA, an inhibitory neurotransmitter that relaxes your nervous system. Magnesium also helps boost your melatonin production
  • Detoxification and reduces damage from electromagnetic fields
  • Regulate blood sugar and improve insulin sensitivity, potentially protecting against Type 2 diabetes

Magnesium is required for activation of vitamin D

Magnesium is also a component necessary for the activation of vitamin D,12,13,14 and deficiency may hamper your ability to convert vitamin D from sun exposure and/or oral supplementation.

According to Mohammed Razzaque, professor of pathology at Lake Erie College of Osteopathic Medicine in Pennsylvania, coauthor of a study published in The Journal of the American Osteopathic Association (JAOA) in March 2018,15 “By consuming an optimal amount of magnesium, one may be able to lower the risks of vitamin D deficiency, and reduce the dependency on vitamin D supplements.”

Interestingly, the first paper I ever had published, back in 1985, was also in the JAOA. My paper was about the use of calcium to control hypertension, but if I had written the paper this century, it most certainly would have been about the use of magnesium for that purpose.16

A second study,17 published in The American Journal of Clinical Nutrition in December 2018 also concluded that your magnesium status plays an important role in your vitamin D status. Overall, people with high magnesium intake were less likely to have low vitamin D. They also had a lower mortality risk from cardiovascular disease and bowel cancer.

As explained by Dr. Qi Dai, professor of medicine at Vanderbilt University Medical Center and the lead author of this study, “Magnesium deficiency shuts down the vitamin D synthesis and metabolism pathway.” What’s more, magnesium was found to have a regulating effect, raising and lowering vitamin D based on baseline levels.

In people who had a baseline vitamin D level of 30 ng/mL (75 nmol/L) or below, magnesium supplementation raised their vitamin D level. However, in those who started out with higher vitamin D levels (50 ng/mL or 125 nmol/L), magnesium supplementation lowered their vitamin D.

Magnesium for brain health and neurological functioning

Magnesium is also crucial for optimal brain function, and is a common culprit in neurological ailments, including:

Migraines18,19,20 Researchers have noted that empiric treatment with a magnesium supplement is justified for all migraine sufferers.21

Depression — Magnesium plays an important role in depression as it acts as a catalyst for mood-regulating neurotransmitters like serotonin. Research22 published in 2015 found a significant association between very low magnesium intake and depression, especially in younger adults.

Research23 published in PLOS ONE demonstrated magnesium supplementation improved mild-to-moderate depression in adults, with beneficial effects occurring within two weeks of treatment. In fact, the effects of magnesium were comparable to prescription SSRIs in terms of effectiveness, but without any of the side effects associated with these drugs.

Participants in the treatment group received a daily dose of 248 milligrams (mg) of elemental magnesium for six weeks, while controls received no treatment. According to the authors, “It works quickly and is well tolerated without the need for close monitoring for toxicity.”

Memory problems and loss of brain plasticity — Memory impairment occurs when the connections (synapses) between brain cells diminish. While many factors can come into play, magnesium is an important one.

According to Dr. David Perlmutter, a neurologist and fellow of the American College of Nutrition, “magnesium is a critical player in the activation of nerve channels that are involved in synaptic plasticity.”24 Magnesium threonate, which most effectively permeates the blood-brain-barrier, is likely your best choice here.

The specific brain benefits of magnesium threonate were demonstrated in a 2010 study25 published in the journal Neuron, which found this form of magnesium enhanced “learning abilities, working memory, and short- and long-term memory in rats.”

Health benefits of vitamin B6

Like magnesium, vitamin B6 (as well as several other B vitamins) also plays an important role in heart and brain health. It is used in the creation of neurotransmitters, and is required for proper brain development during pregnancy and infancy.26

Vitamins B6, B9 (folate, or folic acid in its synthetic form) and B12 may be particularly important for supporting cognitive function as you age, and have been shown to play a major role in the development of dementia, including Alzheimer’s disease, which is the most serious and lethal form.

A primary mechanism of action here is the suppression of homocysteine,27 which tends to be elevated when you have brain degeneration. High homocysteine has also been implicated in the development of atherosclerosis.28,29

The good news is your body can eliminate homocysteine naturally, provided you’re getting enough B9 (folate), B6 and B12. One study confirming this was published in 2010.30 Participants received either a placebo or 800 micrograms (mcg) of folic acid (the synthetic form of B9), 500 mcg of B12 and 20 mg of B6.

The study was based on the presumption that by controlling homocysteine levels you might be able to reduce brain atrophy, thereby slowing the onset of Alzheimer’s. Indeed, after two years those who received the vitamin-B regimen had significantly less brain shrinkage compared to the placebo group.

A 2013 study31 took this research a step further, showing that not only do B vitamins slow brain shrinkage, but they specifically slow shrinkage in brain regions known to be most severely impacted by Alzheimer’s disease.

As in the previous study, participants taking high doses of folic acid and vitamins B6 and B12 lowered their blood levels of homocysteine, decreasing brain shrinkage by as much as 90%. High doses of vitamins B6, B8 (inositol) and B12 have also been shown to significantly reduce symptoms of schizophrenia, more so than standard drug treatments alone.32 Vitamin B6 is also important for healthy:

  • Metabolism, by helping break down amino acids in the muscles to be used as energy and by converting lactic acid to glucose in your liver
  • Immune system, as it helps create white blood cells that fight infections
  • Hair and skin health, by reducing hair loss and alleviating dermatitis

How to improve your magnesium and vitamin B6 status

The recommended dietary allowance (RDA) for magnesium ranges from 310 mg to 420 mg for adults over the age of 19, depending on age, gender and pregnancy status,33 and the adult RDA for vitamin B6 is between 1.2 mg and 2 mg per day, depending on age and gender.34

Both magnesium and vitamin B6 are abundant in whole foods. Good sources of magnesium include leafy greens, berries, avocado, seeds, nuts and raw cacao nibs. Eating a primarily processed food diet is the primary culprit in magnesium deficiency, and if you fall into this group, you’d be wise to take a magnesium supplement.

Vitamin B6 is abundant in animal foods such as beef and wild-caught salmon, as well as dark leafy greens, papaya, oranges, cantaloupe, sweet potatoes, avocados, bananas, spinach, pistachios and sunflower seeds.35Nutritional yeast is another excellent source.

To learn more about the benefits of magnesium and/or vitamin B6, see “Reasons to Increase Your Magnesium Intake” and “Top Benefits of Vitamin B6.” In those articles, you’ll also find more details about top food sources for these nutrients, and how to identify a possible deficiency.

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