Life Extension Magazine January 2014
Turn Off the Cytokine Switch
By Morris Eagleton
In a remarkable series of discoveries, scientists have uncovered the main biochemical “switch” that turns on many of the chronic diseases of aging.
Known as HMGB1 (for “High Mobility Group Box-1”), this intriguing protein molecule triggers the release of the cytokines—a collection of chemical signals—that generate inflammation in your body.1
And as inflammation accumulates, aging accelerates, to the point that most scientists now speak about “inflammaging” as a single entity that underlies disorders that cause premature death, including conditions ranging from diabetes and atherosclerosis to lung disease and cancer, to name just a few.2-4
In an exciting new development, the discovery of HMGB1 as the switch that turns “on” accelerated aging has led to the development of a safe and effective means of turning “off” that switch and reducing premature senescence.
Research over the past few years has demonstrated that two natural ingredients can directly control HMGB1, switching off the massive cytokine flow that generates age-related inflammation and leads to disease and premature death.
Tested in prestigious hospital research laboratories, two plant extracts, mung bean seed coat and green tea, extended life spans and increased survival rate caused by inflammation in blood poisoning (sepsis) by up to 82%.5,6
This combination of natural ingredients can reduce total body exposure to the ravages of inflammation. By doing so, maturing individuals can protect themselves from accelerated aging, guard against inflammation-induced chronic disorders, and live a longer and more productive life.
HMGB1: The “Cytokine Switch”
Inflammation is a helpful reaction when your body is under attack by germs, or following an injury. Under those circumstances, inflammation represents the first step in the healing process, bringing in white blood cells to clean up after the invaders have been destroyed and boosting blood supply to the injured or damaged area.
But ongoing, chronic inflammation is another matter entirely—it has been linked with many age-related, lifespan-shortening disorders, including heart disease, cancer, chronic obstructive pulmonary disease (COPD), diabetes, and others.3,4
Scientists have now discovered that HMGB1 has been implicated in acute inflammation—and that sustained high levels of HMGB1 are responsible for maintaining the chronic inflammation that speeds the aging process.1
It turns out that HMGB1 inside your body cells is very much a good thing; it helps regulate the way your genes are expressed, acting as a kind of “general manager” of cellular processes.7 But when a cell is damaged, its contents of HMGB1 leak out, and trouble begins.8
HMGB1 And The “Cytokine Storm”
This released HMGB1 binds to receptor molecules on immune system cells, acting as a “danger signal” that triggers them to release cytokines.1,7 Cytokines, in turn, are chemical signaling molecules that call in still more white blood cells, which release still more cytokines, in a deadly frenzy of activity.
Taken to the extreme, such activity can result in a “cytokine storm,” a massive, body-wide release of cytokines that can shut down your body’s entire system.9-11 During a cytokine storm, which can be potentially lethal, over 150 inflammatory mediators are released throughout the body.12 We dealt with the prospect of a cytokine storm on a large scale during the 2003 outbreak of SARS (“severe acute respiratory syndrome”) and more recently in 2009 during the H1N1 outbreak.13-15
Fortunately, most of us never have to face a true cytokine storm. Instead, we experience the cumulative effects of lower levels of cytokines, maintaining a steady and rising drumbeat of chronic inflammation that destroys our blood vessels, bones, and joints, promotes cancer development, and lays waste to our brain cells to rob us of memory and cognition.1,16-45
Elevated HMGB1 levels have now been found to be associated with many acute and chronic inflammation-related disorders, including:
- Asthma and chronic obstructive pulmonary disease (COPD)16-19
- Atherosclerosis, lipid disturbances, and their consequences, coronary artery disease, heart attacks, strokes, and congestive heart failure20-28
- Autoimmune disorders, including lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes, and others29-34
- Inflammatory bowel diseases (Crohn’s disease and ulcerative colitis)38,39
- Neurodegenerative disorders21,23,29
- Surgical procedures, even those without obvious complications43
- Trauma, including hemorrhagic shock, traumatic brain injury, acute lung injury and bone fractures41,42,44,45
- Viral and other infections46,47
Fighting HMGB1 To Reduce Inflammation
Impeding HMGB1 is turning out to be a powerful means of slowing and reversing inflammatory processes, with laboratory results showing an increase in survival rate in the face of ongoing inflammatory damage.5,6 Scientists are just now beginning to make strides in the fight against inflammation in asthma, in arthritis, in multiple sclerosis, and in inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), using specialized large molecules (antibodies) that bind HMGB1 and prevent its cytokine-mediated effects.18, 48-55
Don’t expect to see these treatments available from Big Pharma any time soon, though. Therapies employing HMGB1-neutralizing antibodies have shown promise in animal models; however, they have not been tested in clinical trials. Moreover, neutralizing antibody treatments are faced with several challenges, including poor drug response and adverse side effects like acute hypersensitivity reactions.56
But there’s hope for all of us who recognize the importance of suppressing inflammation in pursuit of a long and healthy life. The anti-HMGB1 properties of mung bean seed coat and EGCG from green tea leaf have now been harnessed to tamp down inflammation and slow the accelerated aging that accompanies chronic inflammatory processes.5,6
Since these products are natural and have millenniums of human use to back their safety, you can use them as a daily supplement to gain protection from chronic, inflammation-induced diseases, and slow down certain aging processes in your body.
Both mung bean and green tea are components of traditional Asian cuisine and medicines. Mung bean is an excellent source of protein that, unlike most other beans, is virtually free of flatulence-inducing factors, making it a natural food for the ill.57 And mung bean soup is credited with having “cooling” properties in traditional Chinese medicine, a prescient idea that accords perfectly with present-day discoveries about the bean’s anti-inflammatory properties.58
Green tea has been consumed in China for millennia and has been used as a health aid since at least the 12th century for its many beneficial effects. Today, green tea is known to be one of the most prominent sources of plant polyphenols with anti-inflammatory actions.59
The sources of the anti-inflammatory properties of these two ancient health-promoting substances are becoming increasingly clear under the scrutiny of modern science. Both of these ingredients have been shown to interfere at several different points in the cascade of events that leads to HMGB1 release from stressed or damaged cells, making them especially potent in battling inflammation from several causes, infectious and non-infectious, acute and chronic.5, 6,60-63
The HMGB1-lowering effect of mung bean is found mainly in the seed coat portion of the bean. Mung bean seed coat extract reduces HMGB1 levels both within and outside of immune cells stimulated by bacterial toxins.5 Two flavonoid molecules in particular, vitexin and isovitexin, account for a large part of the anti-HMGB1 activity of the extract. Studies show, however, that these molecules are effective only in crude extracts of the bean; commercially purified versions are much less useful.5
Fed to rats both before and after exposure to heat stress (swimming in 104°F water), mung bean seed coat extract reduced blood markers of excessive oxidant stress, while also strengthening the body’s natural antioxidant defense system.58 These findings bear out the traditional view of mung bean as a “cooling” food.
Green tea extract dose-dependently attenuates HMGB1 release from cells exposed to bacterial toxins; this activity was later found to be produced by EGCG, the major beneficial component in green tea.6 And EGCG drives down HMGB1 release in immune cells even when given 2 to 6 hours after exposure of cells to the toxin.6,62
Mung bean seed coat extract and EGCG are available in oral form, making their combination an effective HMGB1-blocking therapy.5,6
Mung Bean and Green Tea
The most dramatic illustration of how mung bean seed coat and EGCG from green tea leaves can save lives comes from two recent studies at the Department of Emergency Medicine, North Shore University Hospital on Long Island, New York; University School of Medicine, New York; and the Feinstein Institute for Medical Research, Manhasset, New York.5,6
Researchers were interested in the therapeutic role of targeting HMGB1 in sepsis. Sepsis, commonly called blood poisoning, kills more than 225,000 Americans (mostly older adults) every year in intensive care units, despite modern antibiotics and life-saving technologies.64
It is also a useful model for understanding the role of anti-HMGB1 therapies in the most extreme example of out-of-control inflammation. In sepsis, massive amounts of HMGB1 trigger an outpouring of cytokines. It is this resulting inflammation, and not the infecting germ, that ultimately kills the patient.65,66 And once those cytokines are on the loose, it’s typically too late to fight back with anti-cytokine therapies.67-69
Instead of turning to expensive and dangerous anti-HMGB1 antibodies, however, as other researchers had done, researchers at the North Shore University Hospital and Feinstein Institute for Medical Research chose to study mung bean seed coat extract and EGCG from green tea leaf extract, based on their known anti-HMGB1 activities.
The experiments were simple but dramatic. The researchers first induced sepsis in laboratory mice, dooming them to almost certain death without intervention.5,6 In half of the mice, however, the researchers did intervene—but not until 24 hours after the induction of sepsis.
In their first experiment, the scientists gave the mice EGCG from green tea, or a salt-water control, at 24, 48, and 72 hours following the onset of sepsis.6
There was no other intervention: no antibiotics, no IV fluids, no ICU drugs or equipment.
As described in Figure 1, repeated administration of EGCG conferred protection against lethal sepsis by significantly increasing the survival rate of animals from 53% to 82%.6
Encouraged by this result, the researchers turned to mung bean seed coat extract.5 You can see this outcome in Figure 2; using the same experimental design as in the previous study, the mice were given the extract (or saline control) beginning the day after induction of sepsis. Mung bean seed coat conferred a significant protection against lethal sepsis, increasing animal survival rates from nearly 30% to just over 70%.5
It’s impossible to overstate the significance of these results. In unprecedented research, septic shock was significantly prevented, and animals were rescued from an otherwise likely death, using a simple, natural, oral treatment. The secret to their success was the sharp drop in HMGB1 levels induced by both EGCG and mung bean seed coat extract.5,6
How does all this relate to you?
Most of us will, mercifully, never have to deal with sepsis or the out-of-control inflammation that it can produce. The combination of EGCG and mung bean seed coat that contain such potent HMGB1-suppressing activity means that we can all benefit from reduced levels of total-body chronic inflammation.
Chronic inflammation has recently been shown to reduce the length of telomeres, the “living fuses” in our chromosomes that shorten with age.70,71 Thus, reduced chronic inflammation might translate to a longer and healthier life. This is a very literal demonstration of how chronic inflammation acts as an aging accelerator, fueled by excessively high HMGB1 levels. Mung bean seed coat extract and EGCG might help you to literally slow down your aging processes and prolong your life.