the Archives: This article originally appeared in the November
2006 issue of the Townsend Letter.
Exercise is a readily accessible, safe,
and inexpensive anti-inflammatory medicine. Inflammation is the
body's natural means of stimulating healing; but when continuous
and chronic, it becomes damaging and detrimental to health. Properly
performed, exercise releases signaling molecules that stimulate
a unique healing response which couples both inflammatory and anti-inflammatory
mechanisms to repair, regenerate, and grow stronger tissue. Understanding
the history and mechanism behind these effects creates new prescriptive
opportunities for exercise. Unlike drugs, which have single targets
and ignore the weblike interactions in the body, exercise works
with the body's innate intelligence to produce broadly beneficial
effects that improve whole-body function. High-intensity, short-duration
movement that is tailored to the individual, uses short rest periods,
and engages the whole body may be the chief means of attaining anti-inflammatory
effects from exercise.
The human body was designed for activity and evolved with movement.
The vast majority of human existence was steeped in the harsh realities
of the natural world. Our ancestors did low-intensity activity all
day, every day, and were forced to engage in vigorous movement to
avoid danger and procure food. This extreme physical reality made
injury and infection commonplace. Inflammation produced in response
to physical insults was the body's natural protective mechanism
While inflammation is often thought of as destructive, it is actually
a closely orchestrated event that first produces pain, redness,
swelling, heat, and tissue destruction, but then is followed by
repair. Over the millennia, the human body evolved and used acute
inflammation to heal, repair, and regenerate itself. Movement was
an essential part of this healing and regenerative process. The
unique anti-inflammatory effects of movement have been circumvented
in the modern era. With the arrival of the industrial and technological
revolutions, human movement came to a crawl. This left inflammation
unchecked by the anti-inflammatory and growth-stimulating effects
In modern day, the human body is confronted with persistent stress.
Along with this stressful lifestyle, humans no longer depend on
movement and its growth-stimulating and healing effects. As a result,
acute and controlled inflammation has given way to chronic, low-level
inflammation. This type of inflammation is less detectable by objective
or subjective measures, making it more insidious in nature. The
lifestyle of prehistoric humans had substantial risks, yet their
movement patterns kept chronic inflammation at bay. Without the
balancing effects of exercise, inflammation is allowed to smolder
at a low level, damaging tissue and destroying the quality and quantity
Every time the body moves, muscles release signaling molecules that
communicate to the rest of the body. The endocrine properties of
muscle, like fat, have been confirmed.3,4,6 In the case of muscle,
compounds called myokines are released in response to voluntary
contraction. Myokines are cytokines, yet are derived specifically
from muscle. These myokines give instructions to the body about
how to function, and they hold the key to controlling chronic inflammation.
The most important myokine related to muscle and inflammation is
IL-6. When muscle contracts, IL-6 is released.
IL-6 is a well-known cytokine and has long been thought to be inflammatory
in nature as part of what is known as the inflammatory triad: TNF-alpha,
IL-1, and IL-6. However, IL-6 seems to behave differently depending
on its origin, amount, and other cytokines around it. When released
from muscle, and in high concentrations without TNF-alpha and IL-1,
IL-6 is anti-inflammatory.10,12 In fact, IL-6 acts to reduce the
amount of TNF-alpha and IL-1 in circulation by increasing the cytokine
inhibitors IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors
(sTNFR).5,7,8 IL-1ra antagonizes the IL-1 receptor, decreasing IL-1
effects, while sTNFR binds up TNF-alpha before it can react at its
target cells. At the same time, IL-6 triggers the release of the
major anti-inflammatory cytokine IL-10.7,8
It appears that exercise-induced IL-6 has unique action as opposed
to TNF-alpha-mediated release of IL-6.10 Exercise causes a huge
rise in IL-6, far and above TNF-alpha levels. This is in sharp contrast
to infection or sepsis, which shows an exponential rise in both.
The ratio of IL-6 to TNF-alpha may be the real concern in regard
to chronic inflammation. Epidemiological studies on TNF alpha and
IL-6 genetic polymorphisms support this, showing that those with
the highest TNF alpha and lowest IL-6 levels have the greatest risk
of diabetes.37 Other researchers support TNF alpha as the real inflammatory
culprit.10 They speculate IL-6 levels may be a marker of whole-body
TNF-alpha levels and could be acting in direct opposition to the
more inflammatory cytokines. The IL-6 effect implicates exercise
as a first-line defense against inflammation and may explain the
"counterintuitive" findings on the benefit of resistance
training in highly inflammatory diseases like rheumatoid arthritis.26
IL-6: The Exercise
For some time, science has been searching for a molecule that could
account for the acute metabolic effects of exercise. Exercise reduces
"all cause mortality," due to its effects on the leading
killers: heart disease, diabetes, and cancer.35,36 IL-6 is also
beginning to be shown to be protective against diseases like diabetes.12,14,16
These same diseases have strong links to inflammation, which is
now suspected as a major underlying cause. It has long been thought
that exercise's impact on weight loss was the reason behind
this. However, IL-6 also plays a role as a mediating factor in exercise's
effects on fuel metabolism.1,3,4,6,15 The broad effects IL-6 has
on inflammatory cytokines and fuel metabolism, plus its ability
to "talk" to the brain, liver, and adipose tissue, have
some researchers thinking it is the best candidate for the elusive
As muscle contracts, the genes controlling IL-6 production are turned
on. The degree of IL-6 released from muscle is directly proportional
to the amount of muscle being contracted; the more muscle used,
the greater the response.5,7,38,40 IL-6 also shows a tight relationship
to muscle glycogen and exercise intensity. When muscle sugar stores
begin to decrease, an intensity threshold is breached, and much
larger amounts are released.40 Rising exercise intensity, full-body
muscle contraction, and muscle glycogen depletion are the major
exercise elements enhancing IL-6 release from muscle.11,12,38 These
factors together can induce an increase of plasma IL-6 that is 20-
to 100-fold over resting levels.5,41 When at these levels, IL-6
begins to exert influence over the body, relaying messages about
the metabolic needs of the muscle. In this way, IL-6 acts more like
a hormone than a cytokine, sending communications from muscle to
adipose tissue, immune cells, and the liver. These messages instruct
the body to burn fat, control glucose regulation, inhibit the production
of the pro-inflammatory cytokines, and ultimately generate a fully
anti-inflammatory effect through the release of IL-10.8 IL-10 is
a potent reducer of TNF-alpha and IL-1 in its own right.10
From the above scenario, it should be apparent that the ability
to harness IL-6 through exercise can have a significant effect,
not only on inflammation, but on whole-body fuel usage and tissue
repair. This process is far different than the usual chronic inflammatory
scenario. A situation of chronic inflammation is one where TNF alpha
is elevated along with IL-6 and IL-1. Exercise-induced, muscle-derived
IL-6 shifts the balance, causing a reduction in TNF-alpha and IL-1
with a simultaneous rise in IL-10.
Other Effects of
In addition to its more direct effect, exercise-induced IL-6 has
other secondary effects that account for increased benefits. 11beta
hydroxysteroid dehydrogenase type 1 (11beta HSD1) is an enzyme that
should be on the radar of physicians. It is responsible for the
conversion of cortisone into active cortisol. This cortisol/cortisone
ratio is important in keeping the detrimental effects of cortisol
at bay by deactivating it to cortisone. This enzyme is present in
visceral adipose and is overly active in the overweight and obese.13
This is an important revelation as it points to visceral adipose
tissue as a new site of cortisol production. TNF-alpha and IL-1
beta are both shown to upregulate 11beta HSD1 and contribute to
total glucocorticoid production.13 IL-6 is a potent inhibitor of
both TNF-alpha and IL-1 beta, and the largest amounts are released
through exercise. Intense exercise potentiates these effects by
increasing sympathetic stimulation of alpha 2 receptors as well
as ACTH (adrenocorticotropic hormone), all of which have independent
effects in suppressing HSD1 activity. The ability to blunt the HSD1
enzyme is beneficial in controlling obesity and diabetes, and intense
exercise may be the best way to effect these changes.
In addition to the cytokine effects, IL-6 crosses over into hormonal
action and allows the muscle to "talk" to the adipose
tissue.4 In response to exercise, IL-6 from muscle acts at distant
sites, including the liver and adipose tissue. Its major action
at these sites is to release energy substrate to fuel continued
movement. IL-6 is a potent stimulator of adipose tissue fatty acid
oxidation and is a major factor in liver glycogenolysis.1,4 While
the mechanism for this action has not yet been fully elucidated,
studies have confirmed that IL-6 has direct effects on the expression
of AMP-kinase and hormone sensitive lipase, two chief fuel-regulating
enzymes in human tissue.15,47-48
Finally, IL-6 has the ability to cross the blood-brain barrier,
having direct effects on the brain. In fact, the brain itself produces
IL-6 in response to exercise as well. This sparks curiosity as to
what IL-6 is doing to the brain. Animal studies show that IL-6 is
having a direct and important effect on the brain. These studies
show IL-6 playing a role in appetite regulation, fuel regulation,
and body composition.16
IL-15, The Arnold
Along with IL-6, IL-15 is another myokine that is working to reduce
inflammation in less direct ways. This cytokine works by interacting
with transcriptions factors, such as PPAR delta, decreasing adipose
tissue size while at the same time increasing muscle contractile
elements and size.51-55 The end result will be less adipocytokine
release (inflammation) due to a decreased fat mass, and a higher
potential secretion of myokines (anti-inflammation) due to a greater
It appears that IL-15 is emerging as a potent antiobesity weapon
and may explain why resistance exercise, which does not typically
burn as many calories as aerobic exercise, dramatically affects
body composition. We like to refer to this myokine as the Arnold
Cytokine after Arnold Schwarzenegger, famous bodybuilder/actor,
now governor of California. Bodybuilders are able to develop extremely
lean and muscular physiques while focusing almost all their attention
on high intensity resistance exercise as opposed to aerobic exercise.
Research shows that IL-15 release is twofold higher in type-2 dominated
muscle tissue and that resistance exercise doubles IL-15 concentrations
24 hours after exercise.51,52 This shows a novel mechanism by which
resistance exercise is a potent stimulator of fat burning. The effects
of IL-15 are not the same in type-1 muscle fibers, which dominate
in aerobic activities. IL-15 has profound effects on reducing adipose
tissue size while at the same time acting to increase muscle tissue.
These effects are desirable, since muscle mass is frequently lost
along with fat in aerobic-centered exercise programs.
IL-8 is another myokine that may help the body heal through ability
to build greater blood supply. It is produced whenever the muscle
encounters low oxygen supply, such as when it is undergoing intense
anaerobic exercise. It appears that IL-8 is a potent angiogenic
factor that signals the body to begin to build new blood vessels
to increase blood supply. The muscle release of IL-8 is intuitive
and self-serving for the muscle, allowing the tissue to meet the
demands of activity the next time around. It appears that IL-8,
like IL-6, is associated with intensity of exercise. It is released
in highest concentration as a response to exhaustive aerobic exercise
and during eccentric contraction. The myokine appears to act locally,
inducing the angiogenic effects in the muscle tissue only. This
is in contrast to IL-6 and IL-15, which, despite being cytokines,
cross over into hormonelike action when induced through exercise.56
IL-6's release from muscles cells is not a nervous-system phenomenon
and is not based on muscle injury. It seems the impetus for IL-6
release is mechanical.6,40 In other words, just the act of movement
is all that is required. However, there are ways to amplify IL-6
production during exercise. The science of exercise metabolism now
goes far beyond simple calories. The ability to harness the far-ranging
hormonal and cytokine effects of exercise can be accomplished through
the use of short-duration, high-intensity exercise techniques used
in athletic populations for decades. Although the term "high-intensity"
may give pause, these tools and techniques can be adapted to use
in even the least fit and most inflamed populations.17-26
Before discussing the techniques in this approach to exercise, it
is important to define why short, intense exercise is best. The
damage associated with chronic inflammation is compounded by a lack
of offsetting growth factors. The body produces these growth factors
in response to intense exercise. Testosterone and especially growth
hormone are known to be factors linked closely with intensity. The
word intense, as we use it here, means exercise that is glycogen-depleting;
that is, exercise that significantly reduces the body's muscle and
liver sugar stores. Only two types of exercise are able to produce
these effects: long-duration exercise lasting hours, or short, intense,
sprint-type exercise. There are obvious constraints to prescribing
hour-long exercise sessions, since time shortage is the number one
reason cited for lack of exercise participation. Consequently, short,
intense exercise is not only more beneficial, but more realistic.
In addition, the overall hormonal response to long-duration exercise
is counterproductive, as it raises cortisol levels above the body's
ability to compensate with growth promoters.27-34
High-intensity exercise using short bursts of all-out effort significantly
alters glycogen stores and can be easily managed through the use
of intervals – periods of all-out effort interspersed with
rest. This type of activity is manageable by those considered most
frail in terms of exercise prescription, including chronic obstructive
pulmonary disease (COPD),19-20 postbypass,22 congestive heart failure,23
and even heart transplant patients.18 This type of anaerobic stimulus
more realistically mimics real-world challenges and allows for self-paced
exercise that is safe, tolerable, and more beneficial for many heart
and lung patients.17-25 Cardiac patients also have less risk with
this type of activity, as it has more favorable effects on Stress
Test (ST) segment changes and heart rate variability.21,24-25
This type of exercise also makes sense because it creates a hormonal
environment that produces sustained fat-burning as well as muscle
growth.42-44 The amount of glycogen reduction is directly
correlated to IL-6 release, and high-intensity exercise is shown
to increase IL-6 and catecholamines together.5-6,11,49
Catecholamines have their own independent effect in lowering TNF
alpha and IL-1, synergistically enhancing IL-6. Combining these
known effects with techniques that can deliver the same benefit
in less time presents the opportunity to supply these anti-inflammatory
effects in short time periods.45,46
The most efficient way to generate an ample IL-6 response to exercise
is to combine resistance training and aerobic exercise in one workout.
This allows the body to quickly dip into anaerobic metabolism where
glycogen stores are rapidly depleted to sustain energy. Relying
strictly on aerobic metabolism makes significant glycogen reduction
unlikely in the time periods most people are willing to exercise.
Combination workouts also allow the body to efficiently switch from
aerobic to anaerobic metabolism and back again. This is a useful
metabolic skill, considering that cardiovascular events can be induced
by unexpected anaerobic challenges that the body is not prepared
to handle. Examples would be shoveling the first winter snow or
running to catch an airplane. It is prudent to train this energy
system, and it accomplishes significant risk reduction.17-25
The exercises used also should move away from more conventional
types. Those that involve large muscles and combine multiple joints
stimulate a large amount of muscle contraction and supply a better
stimulus for IL-6 release.6 Hybrid exercises that combine two or
more traditional types of exercise in one movement are able to stimulate
large amounts of muscle and cut down on time in the gym. An example
would be combining a squat exercise with a shoulder press. Rather
than performing the exercises separately, they are merged so that
the completion of the squat is immediately followed by the press
in one single movement. This same principle can be used to create
a whole range of exercises that are more functional, less monotonous,
and more efficient than traditional training methods.
Other useful tools to incorporate into the workout include short
rest periods as well as metabolic and mechanical failure. While
the failure component is not necessary to induce IL-6 release, it
will ensure a large IL-6 surge. The ability to maintain exercise
and the onset of a muscle "burn" is a good indication
the muscle sugar supply is being taxed. The rest periods should
be taken when needed, with exercise being resumed as quickly as
possible. The ability to speak is a good indication of exertion
and usually corresponds to 85% of one's V02 max.50 A person should
push until he has to rest and then rest until he can push again.
Using heart rate measures coupled with exertion scores based on
the ability to speak, exercise participants can create a safe workout
that delivers a large dose of anti-inflammatory mediators.
The easiest way to incorporate the short rest periods and failure
concept is to use supersets and hybrid movements. A superset consists
of two exercises done back to back without rest. A short cycle can
be set up so that three to four exercises are done back to back
in succession and repeated until the participant must stop or reaches
her limit. Once that occurs, the participant rests until she can
continue again, using the ability to talk as a guide. The use of
a stopwatch allows the exerciser to time himself for ten, 20, or
30 minutes. This creates an efficient workout that induces a large
IL-6 response and also excels at increased fat-burning and optimal
Inflammation is one of the body's natural protective mechanisms,
but when it becomes chronic, it can turn destructive. Movement has
historically kept inflammation in check through its anti-inflammatory
mechanisms. As human movement has decreased, chronic inflammation
has become rampant and contributes to all the major killers. The
power of intense exercise to combat inflammation has been illustrated.
A fast-moving workout using full body movements, minimizing rest,
and focusing on glycogen depletion can insure adequate anti-inflammatory
effects. This same style of workout can be tailored to the fitness
level of the participants through the use of a self-controlled interval
format. Heart-rate monitoring and perceived exertion measures based
on the ability to speak allow for a safe and effective workout in
even the frailest. Exercise is an underutilized healing modality
despite its known benefits. With an understanding of its anti-inflammatory
effects, exercise can now be seen as a useful adjunct or first-line
therapy in all diseases of chronic inflammation
This article originally appeared in the
November 2006 issue of the Townsend Letter.
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Jade Teta, ND, CSCS
2522 Reynolda Road
Winston-Salem, NC 27106
Metabolic Effect: 877-88MEFIT