Pilates for Scoliosis

Pilates Instruction for Scoliosis
By Suzanne Martin, PT, DPT

Scoliosis is a chronic spinal condition, not particularly a disease. It’s a hot topic in the Pilates world, and in the hands of a skilled instructor, Pilates can excel in the long-term training needed to help change the many factors involved in the distorted spine and unbalanced musculature associated with scoliosis. In this article, I’ll introduce you to scoliosis and provide some guidelines and Pilates exercises for working with these clients.

Pilates clients are often shocked to learn that scoliosis is not necessarily considered a diagnosis worthy of insurance reimbursement. It tends to be seen as a typical “individual difference” since everyone has some musculoskeletal asymmetry due to the asymmetry of the internal organs and the laterality from right or left-handedness. Plus some people can live quite asymtomatically although they show significant deformities.

Defining Scoliosis
Public health standards in the United States traditionally mandate a screening conducted at each child’s school for children at age 10, at the beginning of the second growth spurt, a time when scoliosis usually begins to show its telltale hump in a forward-bend position. Those with positive screen findings are referred into the medical system. Physicians, either a pediatricians or orthopaedists, make a true medical diagnosis of scoliosis using a radiological determination, called a Cobb angle, drawn on the Xray. The skeleton seen from the side shows four spinal curves, making an ‘S’ curve, which is normally where we see our postural preferences such as sway back, posterior or flat pelvis, rounded shoulders and forward head, which may be learned or inherited. From the back, a normal skeleton should not have much of a lateral deviation. The Cobb angle measures the apices of the most lateral curves seen from the back, and must be greater than 30 degrees to be determined clinically significant. However, even people with “minor” scoliosis can be affected by spasms and general rib, low-back and neck pain that often accompanies an altered biomechanical chain.

One major complication is that even though scoliosis is often thought of as a mere sideways shift in the frontal plane (plane cutting the body from front to back), the reality is that it’s quite 3-dimensional, causing essentially a corkscrewing of the vertebrae, due to the bony constraints of the typical shapes of the vertebrae. Add to that the chicken and egg relationship of the weighty head and the heavy legs to a spiraling spine, and you have a catch-22 of ricocheting forces reinforcing, and camouflaging, the original defect that started the whole problem. Plus, the term scoliosis is really a garbage can term, scooping up many spinal issues into one big container. Adolescent scoliosis is obviously more plastic, and intervention here may possibly change a whole life of a skeleton. Yet mature skeletons (over age 22), are still plastic with some capability for change.

Do No Harm
Have heart. The good news is that Pilates can be a very safe, and ultimately very effective modality for most individuals grappling with the scoliosis dilemma, with one major caveat. Remember: First, do no harm. The hallmarks of scoliosis are trunk weakness and what is called a non-neutral spine. [Fred Mitchell, Jr, DO, defines scoliosis as a Type 1 spinal dysfunction, where groups of vertebrae are distorted laterally, giving some force onto “neutral” spinal segments that typically do not have pressure, hence “non-neutral.”] It pays to be conservative when dealing with a spine that is non-neutral to begin with. Performing exercises “within the frame of the body,” and helping someone to find and re-calibrate a closer postural neutral can be effective and meaningful to someone who is out of line. Don’t underestimate the power of neutral.

What Can Pilates Change About Scoliosis?
One major help is just identifying, and then educating the client about, their particular posture type and working on that. Beware the tunnel vision of only seeing the scoliosis curves and then embarking on a mission to overpower the curves. You likely can’t win, and if you do, did you spasm or throw someone into blinding pain? While it’s true scoliosis may not have a cure, you sure can manage it if you’re smart. One of the best things Pilates instructors can do is give some control back to people by teaching them internal control. Being able to hold your spine from the inside is one huge relief to those of us with soft spines.

Change happens in small increments; this is not a quick fix. I start my clients with a manual therapy treatment that usually can lessen their discomfort quickly and loosen up the fascia so they can begin to set new movement patterns. Finding a manual therapist to be a part of the treatment team is a real plus in the rehabilitation scheme. Acupuncture is also a useful adjunct to alleviate pain and promote better nerve conduction.

When dealing with the non-mature skeleton of the adolescent, less is more. The soft skeleton is very plastic and does not have full development of bony prominences that guard joints from coming out of socket. Children and adolescents often cannot bear medications prescribed for adults due to immature organ systems, and so the same is true with exercise.

The exercises below are not meant for more complex conditions where osteoporosis, spondylolistheis (slipping vertebrae) or herniated or degenerated discs are involved. Remember that anybody over 30 probably has some spinal degeneration starting. Note that you are ultimately responsible for the risks you take with each client.

Avoid the tendency to think larger is better; working in flexion and extension works well. You should expect that rotation and side-bending will always be limited in one direction. Two rules of thumb are to always do both sides when doing asymmetrical work, and secondly, to first go into the direction of least resistance and then go the other way. Hypermobility can be another contributor to scoliosis, and I’ll address this in a future article.

The best place to start with a scoliosis client is with the pelvic foundation: the pelvic floor and inner unit.

Lower-Body Toner
Purpose: Turning the electricity on, starting to balance each side of the pelvis and trunk equally.

Lie on your back with the legs absolutely together, shins in table-top position. Imprint the whole spine into the mat. Lift the groin muscles toward the head. Make “dimples” in the gluteals by squeezing the sitz bones together. Then exhale and begin straightening the legs, feet moving toward the ceiling for 4 slow counts, but stop just short of straightening all the way. Then squeeze more as the knees bend back to table top in 4 slow counts. Repeat 2 more times without releasing the whole time. Do only 3 sets per day; do not strain.

Pelvic Floor Exercise
Purpose: To learn coordination of the inner pelvic muscles with some of the larger muscles as well as balancing the inner thighs, the second spine.

Lie on your back and imprint the whole spine into the mat. Lift the legs one at a time into the table-top position and open the thighs past hip width, being sure to keep the legs in parallel, not external rotation.

Place the hands inside the knees, palms open. Lift the anal muscles toward the head. Squeeze the sitz bones together. Make “dimples” in the gluteals (tense them). Hollow the spine. Press the hands against the legs and the legs against the hands. Go easy. Meet them, don’t beat them. Then in 4 counts slowly press the legs toward each other until they’re about 4 inches apart. Stay and hold, intensifying the contraction, if you can, for 4 breaths. Then release, shake the legs and do 2 more sets. Do this only once per day. Don’t strain.

Hold a resistance band by each end vertically. If you bring the top end toward the bottom end, you’ll see the band buckle. The same is true with the spine; elongating it will give some straightening to what aspect of the spine can be straightened.

Purpose: This exercise teaches segmental elongation and is a great help and reliever for people who sit all day. It increases sitting endurance and can be done inconspicuously to renew postural muscle engagement. It’s also a great exercise to do while sitting in at a red light. Don’t confuse this exercise with simple “bracing” where one increases intra-abdominal pressure; it’s a posture alignment exercise.

Ask the client to slump in a sitting position with the feet dangling off the edge of the Cadillac. Press gently down on the client’s head with the palm of your hand. Give the command to inhale, then exhale and slowly start squeezing the sitz bones together, feeling an imaginary hand lift up the skin of the low back.

Elongation in Supine (Trap Table)
Purpose: To engage the outer units with the inner unit; to disengage the legs from the torso; to find neutral lumbar spine coordinated with thoracic spine.

Place two light springs with foot loops on the sliding bar on the uprights about 3 feet from the mat. Have the client lie on her back and hold onto the uprights. Place the foot loops on the feet, and place the legs in table-top position. Cue the client to inhale, then exhale and press the hands against the uprights as she simultaneously presses the feet out to straighten the legs into the standing position, with the backs of the thighs against the mat. Inhale, break at the hips, keep the lumbar spine neutral and bend the legs to table-top. Exhale, lengthen out, inhale, break and bend. Do this 5 times. Then stay in the lengthened “stand” position for 4 breaths, then bend and come out of the position.

Break Up Laterality
Purpose: To bring the center of gravity more evenly between the feet, to even out pelvic obliquity, to wean a standing pattern away from standing on one preferred leg.

Test which leg a client prefers to stand on and which way they prefer to sway by gently pressing against one side of the pelvis, then the other. Which way is easier? Then take a magic circle and place it on the top of the thigh (greater trochanter) of the side of the direction they prefer, lined up sideways in relation to the wall. Ask the client to step into the ring a bit to make it taut to the wall. Her feet should be parallel, about 4 inches apart. Arms are folded with elbows away from the body in genie position. Then the client presses the ring laterally from the pelvis toward the wall in small pulses. Do about 20 on each side.


Pointer Dog (Scooter Variation)
Purpose: To balance the psoas and improve the motion of the pelvic bones.

Stand with one leg on the side of the Reformer past the bolt of the gears toward the pulleys about 6 inches. Place the ball of the other foot on the shoulder pad. Make sure the forward leg is not touching the side of the reformer. Place the hand on the same side as the foot on the shoulder pad on the shortened foot bar. Round and flex the spine and place the free hand next to the gluteals. Exhale and lengthen out the Reformer leg, straightening the knee off of the carriage mat, as you simultaneously straighten out the free arm in front of you as a result of reaching the spine into a flat, neutral spine. (Hence the pointer-dog look.) Then hold the hand on the Reformer bar against the straightened leg/foot firm as you rainbow the free hand up and back following with your face. Exhale as you round the spine back into the starting position. Do each side 6 times, ending with the long leg on the floor next to the Reformer in relative posterior rotation to counteract the anterior rotation associated with a long leg.


Balloon Breath
Purpose: To stretch the internal fascial compartments of the thoracic cavity and the abdominal cavity, to mobilize the vertebrae and restore normal breathing motion of the spine.

Lie on the mat with the knees bent, or place the legs up on the side of the long box. Let the spine lie easily against the mat; don’t force any position for this exercise. Let the pelvic floor be easy, with no particular instructions. Place one hand on the abdomen, elbow on the mat, and the other hand on the rib cage, elbow on the mat. Inhale as you puff the chest out, letting the stretch reach up into the base of the skull, while simultaneously pulling the abdomen into a hollowed position. Then reverse the action, exhaling, puffing the abdomen out, letting the stretch reach all the way to the tail bone while simultaneously compressing the chest, squeezing the air out of the chest. After 5 or 6 repetitions, try to change the breath pattern, exhaling on the chest expansion and inhaling on the abdominal expansion. The spine should stay flat against the mat throughout the whole exercise.


Purpose: To open the ribs and the vertebra, especially where the scoliosis curves change, to strengthen the isolated flexion and extension of the spinal elements.

Place the long box on the Trap Table just in front of the fuzzy loops. Have the client hold onto the top rails, and walk their feet up onto the box and help them slip their feet into the fuzzy loops, dorsiflexing at the ankles to keep the feet firmly in the loops. Check to see that they feel they can hold their body weight up beforehand by just holding onto the top rails and bending their knees. Use rubber shelf liner if their hands are sweaty. If they prove able, let them go up into the fuzzy loops and alternately arch and curl through a spinal roll. Check for dizziness and be ready to help them out of the loops. I recommend not more than 2-3 repetitions. Less is more, unless they’re very athletic.

Scoliosis presents in many different ways; sometimes you have to help a person where they are. They may not understand what the problem is if they are not in pain. Also, if someone has minor, non-symptomatic scoliosis, not ringing the alarm bell may work just fine if you concentrate on the posture type weaknesses. Most people think Pilates is just a simple group of exercises. Some of the more subtle, somatic-oriented exercises that we consider as fundamentals may be lost on those new to Pilates, or to otherwise seemingly healthy adolescents with short attention spans and who view themselves as invincible. When in doubt, refer them, or guide them into a general Pilates classic mat program. They usually can see quite quickly where their deficits are in exercises, such as the Side Hip Lifts.

Yoga VS Pilates

Yoga vs Pilates – Which is better?

It seems that these days you can hardly turn on a television without hearing someone mention Pilates or Yoga. Articles on Pilates and Yoga fill numerous magazines and it seems “everyone who is anyone” is doing one or the other. Why all the excitement? What is so special about these techniques? What are the similarities and differences between Pilates and Yoga?

Yoga, as we all know it, is aimed to unite the mind, the body, and the spirit. Yogis view that the mind and the body are one, and that if it is given the right tools and taken to the right environment, it can find harmony and heal itself. Yoga therefore is considered therapeutic. It helps you become more aware of your body’s posture, alignment and patterns of movement. It makes the body more flexible and helps you relax even in the midst of a stress stricken environment. This is one of the foremost reasons why people want to start practicing Yoga – to feel more fit, to be more energetic, be happier and peaceful. The Yoga movements are performed, mostly, in a group setting on a special Yoga mat with an aid of a Yoga instructor. The body’s own weight is used for resistance and a great deal of focus is accorded to the flow from one posture into the other. There are many different Yoga styles and they differ in their emphasis. No one style is better than the other. The Style you use is a matter of personal preference or a matter of need.

Yoga Styles and Poses

Vinyasa Yoga, for example, makes use of modified yoga poses that are designed to meet the specific needs of an individual and to enhance healing, flexibility and strength of joints. The poses also intend to promote the feeling of well-being and strength. Practices may also include meditation, reflection, study and other classic elements, but the emphasis of this branch of Yoga practice is on coordinating breath and movement. As you can imagine, given the scope of practice, the inherent therapeutic applications and the heritage of the lineage, the training requirements for teacher certification are extensive.

Pilates seek to reach much the same goals, also via a series of controlled movements. The major difference is that the Pilates technique not only has a full complement of matwork, but it incorporates work on the Pilates machines. The emphasis of the exercises is to strengthen the abdominals, improve posture, stabilize and lengthen the spine, improve balance and overall strength. Pilates gives you a longer, leaner, dancer-like line.

Pilates Works the Whole Body

Unlike many other training programs, Pilates works the whole body, emphasizing control, precision and concentration in both the mind and the body. Movements are not performed rapidly or repeated excessively instead, the focus is on quality not quantity. The abdominal muscles, lower back and buttocks (“powerhouse”) serve as the center of all movement, allowing the rest of the body to move freely. This focus on core stabilization makes one stronger from the inside out and is critical for the advancement of the client. The low impact nature of Pilates makes it ideal for injury prevention and rehabilitation. Its six principles-concentration, control, centering, breathing, flow and precision-train the body to move efficiently with minimal impact on the body. The balance between strength and flexibility creates a healthy, vigorous and symmetrical workout for all muscle groups resulting in a leaner, more balanced, and stronger body.

Working With Yoga and Pilates in Conjunction

If after reading about both techniques you are still left with a question of which of these two fitness techniques is right for you then here is the answer: Do them both in conjunction! The nature of the techniques makes it easy for them to complement each other. Get the stretch from Yoga and keep it from Pilates. Strengthen your abdominals on the reformer and watch your poses improve. Join the breathing techniques of Pilates and meditative aspect of Yoga into your daily routine and see the stress of your everyday life, begin to dissipate. Both techniques are time-proven, established, and with the help of an experienced instructor, you will surely reach the goals you set up for yourself!

The differences between Pilates and yoga have always been an issue of discussion among people who are looking out for the best physical fitness regime for themselves. In fact, Pilates vs. Yoga has become a controversial topic, these days. Let us discuss the differences between Pilates and Yoga in detail, in order to understand the health benefits of yoga and Pilates separately. This would also offer you an idea of what type of physical fitness regime would suit you and offer you maximum health benefits.
Pilates vs. Yoga
Pilates is gaining as much popularity as the age old tradition of maintaining a health fitness regime, yoga. Most people, across the globe are aware of the benefits of yoga and Pilates.Pilates is usually considered to be a physical activity rather than a cardiovascular workout. Both Pilates and yoga usually share the same technology and aim towards developing and strengthening of the muscles. Both the forms of exercises focus on the muscles of the arms, legs, abdomen and back.
Some basic differences for Pilates vs. yoga.
 Yogais a physical fitness regime originated in Northern part of India, in ancient period. The history of yoga dates back to almost five thousand years ago. Pilates is not an ancient practice as yoga. It is just eighty years old and invented by a German athlete, Joseph Pilates. Pilatesmethod, although inspired by certain yoga poses, is a complicated system. It works towards conditioning the entire body. Yoga, however is explained as a lifestyle, instead of just an exercise. It works towards offering a path to physical and mental well-being. It also includes all the exercise routines in conjunction with a healthy diet, relaxation, meditation, and breathing skills.  Pilates focus on developing the core strength inside the body and elongating the spine. This form of exercise would enhance strength and spread awareness on proper posture. Yoga basically emphasizes on the union of body with mind and spirit and works on the whole body. Yoga helps in relieving stress.

 Both Pilates and yoga focus on breathing and concentration. The basic difference is that yoga focuses on employing breathing process on a deeper level. Pilates includes inhaling via nose and exhaling through the mouth and yoga concentrates on utilizing the nose for both inhaling and exhaling.
 Yoga includes many styles and all these styles are usually performed in a group on a yoga mat; with the help of instructions offered by a yoga teacher. Although Pilates work on Pilates mat, but it also emphasizes on certain Pilates machines in order to build machines.
 Pilates does not require any sort of extra props such as blocks, straps and blankets whereas yoga does.
There are several benefits of Pilates yoga. Let us discuss on the various benefits of Pilates and yoga, individually prior to deciding on which one is best.
Benefits of Pilates:
Pilates refreshes your mind and body with the help of some non-strenuous workout. Since, it focuses on proper breathing techniques and instructs on maintaining a correct posture and pelvic alignment, you would be able to learn about the correct body posture and the importance of maintaining one. One can easily learn to control body movements and follow a proper breathing schedule. Remember that proper breathing is extremely essential to reduce stress. Pilates is the best way to build strength without attaining those bulky muscles. Bulky muscles have more tendencies to succumb to injuries. Pilates help in strengthening, lengthening muscles, enhancing muscle elasticity and joint mobility.Pilates would help you developing a flat abdomen and a strong back. Within few weeks of practice, you would feel enhancement in your joint mobility, flexibility and following a better posture.
Benefits of yoga:
Yoga is an exercise pattern that focuses on physical as well as mental well being of an individual. It works towards enhancing flexibility, lubrication of the joints, tendons and ligaments. You would be surprised to know that yoga is the only medium through which you can offer a massage to all the internal glands and organs of your body. This physical fitness system works towards a complete detoxification of the body and toning of the muscles. Yoga is the best way to keep your body away from diseases.
Pilates vs. yoga- which is better?

Since both Pilates and yoga offer immense benefits to health, it is difficult to come to a conclusion on which of these body fitness systems is the better. However, the decision entirely depends on an individual and the body frame he or she possesses. What suits a particular person may not suit you, in the same manner.

Making a choice between Plates and yoga would also depend on the targets you have set for yourself. In case, you are looking for a fitness program that offers you a longer and leaner line, Pilates would be the best option for you and if you are looking for an exercise that would condition your mind and body, yoga is the perfect choice for you.

Doing them both in conjunction would be a better choice. Use the right Pilates equipment to maximise your workout. You can easily enjoy the benefits of both the forms of exercises. Try getting the stretch from yoga and strengthen your abdominals via Pilates.

Try learning the breathing techniques of Pilates and the meditative spirit of yoga and you would definitely experience the relief from stress in your daily life and hectic routine.

In a nutshell, both Pilates and yoga are beneficial for health and compliments each other. None of the physical fitness system has negative or side effects on the body, if performed correctly. The benefits of Pilates and yoga have been alluring many people towards them and millions of people, across the globe have already practiced these exercise and benefited from them. You need to look out for an option that would suit your specific requirements and schedule.

Join a Pilates and yoga classes today and you would definitely benefit from these classes. Pilates and yoga have been introduced to offer relief and provide a better health to human body.

Reversing Age-Associated Immunosenescence
via Exercise

 Immunosenescene and exercise

Marian L. Kohut and David S. Senchina


the human population is living longer than ever before and, consequently, the
study and remediation of age-associated diseases is gaining increasing impor-
tance for both ethical and economic reasons. Numerous interventions have been
suggested to counteract immunosenescence. Physical exercise is one of the more
appealing interventions both in terms of efficacy, cost and logistics.
This review summarizes our current knowledge of ageing, the immune sys-
tem, and exercise, and points the way towards potential avenues for future inves-
tigation. A brief overview of ageing and immune response is provided; more com-
prehensive reviews are published elsewhere
We begin by discussing the effects of ageing on the immune system and its spe-
cific components, using information gleaned from studies of both human and ani-
mal models. We then review data regarding the effects of exercise on immunose-
nescence in geriatric populations, also considering the impact of exercise on acute
and chronic disease states. We conclude by considering the data in total and sug-
gesting directions for additional research.

Decreases in immune responsiveness with age are thought to contribute to the increased
incidence and severity of infectious disease among the elderly. Several interventions, in-
cluding exercise, have been proposed to restore immune function in older populations.

Thefindings from some, but not all studies, support the possibility that exercise may attenuateimmunosenescence. In recent years, the role of exercise in modulating immune response
has been examined using models that may have clinical relevance, such as the response to
vaccines and novel antigens. Taken together, the accumulated data suggest that exercise
may be an efficacious therapy for restoring immune function in the elderly. In general,
long term exercise interventions appear to show the most promise. Exercise related
improvements have been reported with respect to antibody titre, T cell function,
macrophage response, alterations of the TH1/TH2 cytokine balance, the level of pro-inflam-
matory cytokines, and changes in naïve/memory cell ratio. However, current data is mini-
mal, and many questions remain including: the mechanisms that are involved, the potential
clinical impact, the appropriate type or dose of exercise, and whether the benefits extend to
all populations including frail, older adults. This review summarizes the major findings of
these studies and proposes directions for future exploration.

Keywords: Immunosenescence; Exercise; TH1/TH2 cytokines; inflammation

Ageing and the Immune System


Age-related changes in immune function (immunosenescence) have been
explored extensively in humans and a variety of animal models in the last quarter
of a century. Though a large number of the observed changes involve declines in
immune function, the term “immunosenescence” does not necessarily imply a
deficit of immune function but more appropriately a dysregulated state. Various
lymphocyte populations respond to ageing differently. Even within a specified
cell type, individual activities may rise or fall with ageing. Therefore, it is important
to consider immunosenescence in the organism as a whole and at the cellular level.
Many have suggested that immunosenescence may contribute to heightened
disease susceptibility (both infectious and noninfectious) in the elderly. Globally,

Address correspondence to:
Marian L. Kohut HHP/Immunobiology 246 Forker building Iowa State University Ames
IA 50011, Tel 51529/48364 Fax: 51529/48740 Email mkohut@iastate.edu

Components of both the innate and adaptive branches of the immune system are
known to exhibit functional alterations with ageing, as has been demonstrated in
both human and rodent models over the last twenty-five years (16, 35, 52, 76-78,
83-86, 158, 181). Novel investigative tools and insights have allowed the specific
identification of these components and the nature of their changes in recent years.
The T cell population has been studied to the greatest extent and appears to be
most affected by the ageing process (76, 180, 243).
Mechanisms that underlie the age-associated dysregulation are currently
being investigated. The vanguard hypothesis is that decreased expression and
functioning of receptors or signaling rafts (90, 101, 196, 250) and defects in sig-
naling pathways (50, 60, 80, 122, 154, 179, 211, 225, 230, 232) may lead to
altered function in immunosenescence. For example, it has been shown that
NFkB levels are lower in T cells from aged mice compared to young mice
(despite comparable levels of CD3 expression), and that upregulation of kinases
such as protein kinase A (PKA) may lower NFκB expression and consequently
the expression of downstream molecules such as interleukin (IL)-2 or IL-2Rα
(CD25) (232). Various transcripts or proteins may be dysregulated (80). Declines
in function and/or signal-induced relocation of other kinases and accessory mole-
cules within the lymphocytes may instead be impaired with ageing, contributing
further to cell dysfunction (154, 211, 225, 230). It is important to note that
immunosenescent-associated changes in signal transduction are not usually single
events – multiple intermediates or steps of the pathway are jointly effected by
immunosenescence (80, 154). Changes may be further exacerbated by the shift
from naïve to memory T cells in the aged (47, 63, 69, 135, 235) as well as alter-
ations in lymphocyte genesis and development (138). Decreased expression of
cell surface adhesion molecules (CAM) may inhibit cell adhesion, leading to a
diminished immune response (46). Glucose utilization in lymphocytes may also
be diminished with ageing (3). The immune system is not an isolated system in
the living organism. Bidirectional communication with the neuroeondocrine sys-
tem may also impact the effects of age on immune function (144). Based on cur-

8 • Immunosenescence and exercise

rent knowledge, multiple mechanisms likely account for immunosenescence,
including factors intrinsic to the cells of the immune system as well as factors
from other physiological systems.

Immunosenescence and exercise • 9

Innate Immunity

The innate immune response is comprised of cells (such as macrophages, dendritic
cells [DCs], and natural killer [NK] cells) and molecular systems (such as comple-
ment and inflammation) that respond automatically to perceived threats. Our under-
standing of ageing on the innate immune system is still in its infancy as most research
efforts have been directed toward the adaptive immune system (85, 158, 181, 189).
Among the cells of the innate immune system, macrophages have been the
studied to the greatest extent (139). Macrophages serve the immune system in
multiple ways: (1) as antigen-presenting cells; (2) as producers of cytokines,
including molecules involved in inflammation as well as B and T cell activation;
(3) as producers of reactive nitrogen and oxygen species (such as nitric oxide
[NO] and superoxide anion [O2-]) that are harmful to extracellular and intracellu-
lar pathogens; and (4) as cellular debris cleaners, such as cells that have under-
gone apoptosis. Implicit in the above description is that macrophages also serve
as a bridge linking innate and adaptive immunity. It is interesting to note that the
effects of age on macrophage function vary by tissue site (96, 126, 212). Howev-
er, some common themes concerning macrophages and ageing can be discerned
from the collected data.
Peritoneal macrophages isolated from rodents generally display decreased
production of cytokines (IL-1, tumour necrosis factor [TNF]-α,) and reactive
oxygen species when stimulated in vitro with mitogen, receptor-specific ligand,
or virus (3, 22, 23, 43, 109, 121, 126, 196, 239). They also exhibit decreased cyto-
static/cytotoxic, phagocytic, and antitumour activity (23, 58, 121, 239).
Lipopolysaccharide (LPS)-stimulated IL-6 secretion by peritoneal macrophages
in vitro does not change with age, and IL-12 appears to increase (13, 126).
Macrophages from older mice, however, do produce greater amounts of PGE2
compared with young mice, and PGE2 is known to suppress T cell effector func-
tions (14).
In contrast, stimulated murine alveolar and splenic macrophages generally
produce higher levels of cytokines (IL-1β, TNFα, IL-6, IL-12) and nitric oxide
when compared with younger counterparts (67, 96, 126, 208, 228). Exceptions to
these general trends have been recorded (102, 122, 128). A more detailed compar-
ison of the accumulated data has been presented elsewhere (126). These findings
suggest that “environmental” factors specific to a tissue site may influence age-
related changes in macrophage function.
To assay macrophage functions in humans, typically peripheral blood
mononuclear cells (PBMCs; includes lymphocytes and monocytes) are collect-
ed, and macrophage function is inferred based on experimental constraints and
outcomes measured. Using this methodology, macrophage function is indistin-
guishable from that of monocytes.
PBMCs from older humans stimulated with mitogen in vitro demonstrate
enhanced or suppressed cytokine production on a per-cytokine basis. Production
of interleukins such as IL-1β, IL-6, IL-8, IL-10, and IL-12 are increased upon

ageing (36, 49, 68, 198, 200), whereas production of the cytokine IFN-α is dimin-
ished upon ageing (89, 200). However, some human studies suggest that ageing is
not associated with an increase in pro-inflammatory cytokines such as IL-6 or
TNF-α when health status is taken into account (13, 166).
As macrophages carry out so many critical functions, it has been repeatedly
suggested that immunosenescence-associated changes in macrophage function
may contribute to older hosts’ decreased capacity to clear infections (158, 181).
Macrophages that are not as efficient at presenting antigen or at producing
immune cell-stimulatory cytokines would delay an efficient adaptive immune
response. Similarly, macrophages with diminished inflammatory cytokine or
reactive oxygen species manufacturing capacity would allow pathogens greater
opportunities in the host. Changes such as these may be in part responsible for
higher mortality rates due to infections such as influenza and pneumonia in the
elderly (253), and may explain the diminished efficacy of vaccination in this pop-
ulation (82).
To better understand the link between macrophages, immunosenescence,
and infection, both experimental animal models of infection and observational
studies in infected humans have been employed. Macrophage antiviral resistance
may be increased with age (126). In models of bacterial infection, no differences
have been observed between the response of macrophages from young and old
mice (67, 197). Human models of infection have also been utilized to explore
age-associated changes in macrophage function. Cytokine production in response
to respiratory syncytial virus (RSV) in vitro is diminished in older volunteers
compared to younger volunteers (140). When groups of old and young patients
suffering bacterial pneumonia were compared, it was discovered that older
patients have lower acute phase levels of several cytokines when compared to
younger counterparts (89).
Dendritic cells (DCs) are another class of antigen-presenting cells impor-
tant for activating T cells and also B cells. Activated DCs may be found in lym-
phoid tissue whereas unactivated macrophages lie throughout the peripheral tis-
sues; once activated, they migrate to lymphoid tissue. Besides strict presentation
of antigens DCs also serve as repositories of antigen, which they release over
time to stimulate receptive lymphocytes in the form of iccosomes. Using rodent
models, it has been shown that iccosome release is hampered in older mice and
that this contributes to a diminished secondary antibody response in older mice
(29), likely due in part to DCs inability to induce sufficient germinal centers in
lymphoid tissue (7). Declines in DC surface expression of markers such as FcγRII
may affect immune synapse formation with surface molecules on target cells,
such as the B-cell receptor (BCR), and promote cell inactivation via immune
tyrosine-based inhibitor motifs (ITIMs) rather than activation (7). In contrast to
these results, another team has shown human monocyte-derived DCs to be similar
in function, morphology, and phenotype between young and old humans (143). It
was additionally demonstrated that these DCs were able to stimulate senescent T
cells to activity whereas monocytes could not (143).
With ageing, numbers of natural killer (NK) cells in the peripheral blood
decreases (221), and cell subset demographics are noticeably altered (132),
including an increase in percentage of memory NK cells (220). As their name
suggests, NK cells kill other cells through cytotoxic granule release. NK cell

10 • Immunosenescence and exercise

function may increase or decrease with age depending on the parameter under
scrutiny (189, 221). Further, total NK cell pool activity is maintained with ageing
though per cell killing activity, and proliferative capacity declines (220). The ability
to respond to IL-2 is maintained, dependent on functional outcome measure (220).
The final cell we will consider in this section is the neutrophil, a phagocyt-
ic granulocyte that makes up the largest portion of the white blood cell pool in
humans. A study comparing the effects of age on neutrophil function in human
males has shown that with increasing age, neutrophil phagocytosis increases
(234) whereas neutrophil (granulocyte) superoxide anion production either
decreases (160, 189) or increases (234) contingent on the stimulus employed.
Granulocyte cytokine production is also heightened in centenarians as compared
to middle-aged adults (160). Neutrophil chemotaxis may decline with age (217).
Compared to neutrophils from young individuals, neutrophils from aged individ-
uals are not so easily rescued from apoptosis (189).

Immunosenescence and exercise • 11

Adaptive Immunity

Adaptive immunity is constituted by antigen-specific cells such as B-cells and T-
cells and the cytokines they secrete, but also employs members of the innate
immune system in its efforts as well (181). Due to a larger volume of research,
more is known about the effects of age on this branch of the immune system
(158). Because the adaptive branch of the immune system is dependent on the
innate branch for response initiation, there are two concerns: 1) cells of the adap-
tive immune system are themselves directly affected by immunosenescence-asso-
ciated changes and, 2) diminished innate system function may also impair the
ability of B and T cells to respond to a threat.
Numbers of circulating B cells (the progenitors to antibody-secreting plas-
ma cells) decline with age; germinal center B cell production also diminishes (7,
95, 204, 252). In a classic paper, investigators isolated B cells from young (~25
year old) and elderly (~85 year old) adults, stimulated them repeatedly with a
Staphylococcus protein, and then looked for differences in B cell function. They
found that B cells from older adults had similar proliferative ability but dimin-
ished plasma cell differentiation capacity as compared to young adults (62). This
inability to differentiate was not due to dysfunctional T cell stimulation as co-cul-
ture experiments demonstrated (62). Some defects of ageing appear to be due to
changes intrinsic to B cells. For example, signal transduction involving the B cell
receptor may decline with age (242). Alternatively, cytokine production by B
cells may be altered by changes in behaviour of other lymphocytes: abnormally
high constitutive production of IL-12 by macrophages has been experimentally
shown to drive abnormally high IL-6 and IL-10 production levels in B cells (224).
Plasma cell-produced antibody (Ab; also known as immunoglobulin or Ig)
concentrations may or may not decrease with age, but the proportion of function-
al antibody does decline (219). This may be due in part, to dysfunctional stimula-
tion (such as by DCs or macrophages) as described earlier (7, 29). In general,
lower antibody titre (192) and reduced affinity have been reported (168). Howev-
er, antibody subclass responses are not universally affected by ageing. Following
up on a study reporting impaired IgG production in response to inactivated
influenza vaccination in people, it was demonstrated that ageing decreased IgG1,

but not IgG3, responses (191). However, the IgG1 subclass is best correlated with
haemagglutinin-inhibiting activity (88). Similarly, IgG1 and IgG2 subclass ratios
changes with age when humans are given pneumococcal polysaccharide vaccina-
tion (141). In one study, researchers probed serum samples from older adults for
antibody response to common bacterial, viral, and food antigens and found no dif-
ferences in serum antibody concentrations between individuals in their mid-60s to
mid-80s compared to still older individuals (24). Following a second homoge-
neously old population for 4 years, the same scientists found no overall changes
in antibody titres to the same antigens from the beginning to the end of the study
(24). Further research on the level of protection afforded by antibody titre is need-
ed to determine the clinical significance of altered antibody titre and subclass.
Most changes associated with immunosenescence involve a diverse class of
cells known as T cells. T cells all share in common the expression of the surface
marker CD3. However, within CD3 cells, two principal types of T cell may be
distinguished. CD4-expressing T cells are also known as helper cells. These cells
secrete many important cytokines and play crucial roles in stimulating other cells.
CD4 cells themselves can be categorized on the basis of their cytokinetic profile:
TH1 (Type 1), TH2 (Type 2), or TH0 cells. Each group produces its own arsenal of
cytokines: IFN-γ, IL-2, and IL-12 in the case of TH1; IL-4, IL-6, and IL-10 in the
case of TH2, and both TH1/TH2 cytokines in the case of TH0 (165, 200). The TH1
response is important in assisting CD8+ T cell activation, whereas the TH2
response drives B cell activation and antibody generation (210). CD8-expressing
T cells are also known as killer T cells or cytotoxic T lymphocytes (CTLs), and
these cells are involved in killing other infected cells through the release of cyto-
toxic molecules. CD4 cells and CD8 cells are not affected homogeneously by
immunosenescence, but some age-related changes are common to both (205).
Both CD4 and CD8 cells can be characterized as naïve (never having
encountered antigen), effector (currently involved in an immune response), or
memory (having been involved in an immune response previously but now wait-
ing in case the same immune threat reappears). Changes in T cell number and
function (i.e., naïve:memory ratios) are believed to play a substantial role in the
age-associated decline in immune response (95, 137, 158, 202, 222). Much of this
change is believed to be related to thymus involution and consequential loss of
function with ageing (76, 183, 186, 204, 207, 217). Overall T cell numbers may
decline with ageing, although not linearly, and some subpopulations increase
whereas others decrease (235). T-cell antigen-recognizing receptors (T-cell recep-
tors or TCRs) fall into two types, α:β and γ:δ, and relative numbers of α:β versus
γ:δ T cells change with ageing (207). α:β T cell subset demographics are also
altered with ageing, including a substantial drop in the relative number of naïve
cells and a corollary increase in memory cells (69, 202). Beyond TCRs, T cells
from older adults also express lower levels of other surface molecules such as
CD25 (IL-2Rα), CD38 (a B- and T-cell marker), CD71 (a transferrin receptor
present on all activated/proliferating lymphocytes), and HLA-DR (248).
Besides phenotypic changes at the level of the cell surface, immunosenes-
cence also involves intracellular changes on the molecular level. Antigen is pre-
sented to T cells via major histocompatibility complex molecules, and it has been
shown that aged T cells have a decreased ability to respond to antigen as com-
pared to younger T cells (207). One potential explanation for this is that T cells

12 • Immunosenescence and exercise

from older individuals are less efficient at assembling a signaling complex at the
site of antigen presentation (225). Dysregulation of other intracellular signaling
molecules such as PKA protein kinase C (PKC), and IκB influence gene expres-
sion and consequently T cell activity (173, 232, 233). Within 5 minutes of initial
activation, T cells from old mice showed diminished intracellular calcium levels
compared to young controls, suggesting deficiencies in signaling-associated ion
movement (159).
Immunosenescence is associated with increased frequency of apoptosis (a
form of programmed cellular suicide) in T cells overall. Heightened expression
levels of “death receptors” and associated downstream molecules are associated
with ageing and are likely explanations for this phenomenon (93, 94, 155). This
effect has been shown to be specific to certain CD45-expressing T-cell subpopu-
lations (CD45 is a tyrosine phosphatase) (100). Evidence suggests that T cells
from young humans use different apoptotic pathways than those from older
humans, implying that immunosenescence is also associated with a switch in
apoptotic pathways (237). But critical recent findings also suggest that T cells
from aged mice may not undergo adequate apoptosis during infection, leading to
increased morbidity in older hosts (112). The memory-laden T cell pool of the
aged individual may contain too many self-preserving memory T cells that take
up space in the T cell pool necessary for naïve cells to respond to the infection.
Ageing is associated with the accumulation of viruses encountered through-
out life that are never totally cleared from the body (such as herpes virus or Vari-
cella, the cause of chickenpox and shingles). Chronic stimulation by these resi-
dent viruses may lead to the accumulation of dysfunctional and/or senescent T
cells (61, 95, 107, 175, 178). This is corroborated by studies of the NK cell mark-
er on T cells (221, 226) and studies investigating defective IL-2 secretion by aged
T cells (107).
Proliferative responses of T cells have been shown to be much lower in
older adults as compared to younger counterparts, that may be due in part, to
altered cytokines (36, 79, 149, 200, 217). It has been shown that PBMC produc-
tion of IL-10 is higher in elders, contributing to the impairment of T cell prolifer-
ation (36) IL-2 stimulates T cell proliferation. Age-related reductions in T cell
proliferation have also been correlated with decreases in both IL-2 and soluble
IL-2R (200). Current data suggests that although IL-2Rα (CD25) expression lev-
els on T cell surfaces appear unchanged (200), the affinities of these receptors
may be lowered in immunosenescence (79); however, others contend that CD25
expression levels do diminish with ageing (248). Regardless, reduction in IL-2
does not correlate with changes in all T-cell parameters (65). The elevated
macrophage production of PGE2 associated with ageing, is also known to quell
numerous T functions (14); inhibition on PGE2 can partially restore T-cell prolif-
eration (97). Similarly, if cyclooxygenase is inhibited with indomethacin, T-cell
proliferation is improved (97).
Cytokine production by CD4+ T cells changes with ageing. Individual stud-
ies utilizing cells collected from the peripheral blood of humans and stimulated in
vitro with mitogen or virus have shown that, in general, levels of TH1 cytokines
(IL-2, IL-12, IFN-γ) decrease with age, but levels of TH2 cytokines (IL-4, IL-10)
increase with age as compared to younger counterparts (34, 106, 107, 174, 195,
200, 210, 217). However, other studies have failed to demonstrate an age-related

Immunosenescence and exercise • 13

shift in preference towards one class of cytokine over another (20, 118), or have
shown simply a cross-CD4-subclass heterogeneous shift to a TH1/TH2 imbalance
(133). A recent review of the data concluded that the current findings were incon-
sistent regarding a preference towards a Type 1 or a Type 2 response with ageing
and more appropriately reflected simply an age-associated imbalance (81).
The age-related phenotypic and function changes in CD4+ cells include
altered expression of chemokines from the CCR and CXCR classes (161).
Immunosenescent CD4+ cells show a loss in CD28 expression, a costimulatory
molecule required for proliferation (241). The diminished capacity of CD4+ cells
to respond to antigen-presenting cells or mitogen is possibly due in part to dimin-
ished tyrosine phosphorylation capacity via decreased Tyrosene kenase t56 (Lck)
or other molecule activity (211, 230).
All of these changes relate to altered functional capacity in CD4+ T cells
associated with immunosenescence. For instance, naïve T cell function drops with
age: upon first encounter with antigen, naïve cells from older mice produce less
cytokine, proliferate less, and show lower levels of helper function compared to
naïve T cells from young mice (98). Aged naïve CD4+ cells can gain partial
restoration of function in the presence of supplemental IL-2, but are unable to
produce normal levels of the cytokine on their own, implying that some perma-
nent change blocking T cell IL-2 production occurs during ageing (99). Not only
do CD4+ T cells themselves demonstrate increasing unresponsiveness with age,
but due to their dysregulated state they may actually suppress the function of
other cells instead of promoting it (213).
CD8+ T cells are likewise known to change with ageing (58), but in some
different ways than CD4+ T cells. Cytokine production by CD8+ cells may also
be considered using the Type 1/2 dichotomy even though these cells harbor no
helper T cell functions. Naïve, effector, and memory human CD8+ T cells all pro-
duce significantly higher amounts of TH1 cytokines such as IFN-γ, IL-2, and
TNF-α, whereas only memory CD8+ T cells produce significantly higher
amounts of TH2 cytokines such as IL-4, IL-6, and IL-10 (251). Similarly, if CD8
cells from young and old mice are given equal stimulation and their production of
cytokines are compared, cells from older mice produce more of IL-4, IFN-γ, and
TNF-α, but not IL-2 (163). Thus immunosenescence affects cytokine production
by CD4+ T cells and CD8+ T cells in a different manner.
Molecular and phenotypic changes associated with immunosenescence and
their functional consequences have similarly been determined in CD8+ cells.
CD8+ T cell subset demographics change during the course of ageing (63, 69).
Changes in subset demographics have been linked to functional changes: intracel-
lular cytokine staining has revealed that the age-associated increase in IFN-γ pro-

duction by CD8+ T cells (63) may largely be due to the CD8+highCD28 CD57+ T
cell population, which expands during ageing (9). Phenotypic changes such as
loss of CD28 expression are linked to decreased proliferative ability (56, 57).
Intracellularly, CD8+ cells show decreased phosphorylation capacity in response
to mitogen (211). CTL activity (such as Granzyme B production) and memory
declines with ageing as has been shown using influenza A virus in humans (150,
153, 190) or models of delayed-type hypersensitivity reactions in mice (15).
Several age-associated changes occurring in γδ T cells have been investigat-
ed with the main finding that ageing does not affect γδ T cells homogeneously.

14 • Immunosenescence and exercise

Peripheral blood γδ T cell numbers decline with age; concurrently, a larger pro-
portion of cells express the CD69+ marker of activation (201). Relative numbers
and proportions of γδ T cell subsets change with time and some exhibit reduced
proliferative abilities, but cytotoxic abilities are maintained with age (4). TNF-α,
but not IFN-γ, production increases with age in this group (4).
Another unusual class of T cells are the NK T cells, which have an unvari-
ant αβ receptor but also express the NK marker (189). With age numbers of NK T
cells increase, as does their ability to produce IL-4 (189). It is thought that chron-
ic stimulation by viruses that are never totally cleared by the host (mentioned ear-
lier) may cause increases in NK marker expression on T cells and thus formation
of immunosenescent NK T cells (221, 226).

Functional Relevance of Immunosenescence
It has been proposed that immunosenescence may explain the increased suscepti-
bility of older adults to bacterial (such as pneumonia) and viral (such as influen-
za) infections (35, 57, 83, 87, 156, 200), as well as higher rates of autoimmune
disease and/or inflammatory conditions (inflamm-ageing) (25, 77, 83, 243).
Infection is often more severe in elderlies, sometimes manifesting symptoms
unique to this population (83). Immunosenescence may put older adults at
increased risk for certain types of cancer (16), but some evidence suggests that
humans in their 90s or above (centenarians) may actually become more resistant
to cancer due to additional changes with ageing (40, 95). Low levels of constitu-
tive inflammation may be due to immunosenescence-associated alterations in
plasma protein synthesis, including acute phase proteins as has been shown in rats
(177), or constitutive expression of inflammatory cytokines such as IL-1 and
TNF-α (25, 198, 200).
Numerous interventions have been suggested to counteract age-associated
immunosenescence (18, 104), including exercise (see references cited in next sec-
tion), vaccination (88, 119), caloric restriction (59, 161, 223, 236), dietary or
herbal supplementation, including antioxidants such as vitamin E (14, 103, 104,
111, 162, 209), hormone manipulation (104), and other immunomanipulative
techniques (6, 52, 104, 105, 186). Excluding exercise for the moment, the most
studied of these interventions has been vaccination, typically against either
influenza or pneumonia.
It has been demonstrated both clinically and experimentally that vaccine
efficacy rates are lower in older adults (35, 119, 151, 164), though they signifi-
cantly reduce hospitalizations and mortality (145, 156, 172). Several of the
immunosenescence-associated changes detailed earlier are believed to be respon-
sible for this. Impaired DC function affects not only its ability to present antigen
but also the effector capabilities of its targets, B cells and T cells (7). Plasma cell
antibody response to vaccination is thus diminished, resulting in decreased anti-
body titres in blood or secretions (192, 217). Less naïve T cells and more memory
cells, a large proportion of which are partially dysfunctional, impair vaccine
response (48). CTL function, essential for viral clearance, also declines with age
an may abrogate a robust vaccine response, but this too is contingent on certain
factors such as strain of virus (57, 153, 192). Lower levels of cytokine production
in response to vaccination, such as IFN-γ (175) and IL-2 in older vaccinees, may
correlate with some (152) but not all immune parameters (65). Other researchers

Immunosenescence and exercise • 15

have found no differences in the serum levels of influenza vaccine-stimulated IL-
6 and IL-10 across ages (131).
Using an aged mouse model, researchers found several immune parameters
impaired following intranasal challenge with influenza, including NK cell activi-
ty, CTL activity, and IFN-γ and IL-12 production (51). Virus-specific antibody
and IL-4 production, by contrast, were higher, although antibody titres were not
high enough to confer adequate protection (51). It has also been shown in aged
mice that so many memory T cells exist than upon virus infection, not enough T
cells undergo apoptosis to provide space for virus-specific effector and/or memo-
ry cells to proliferate (112).

Exercise and Immunosenescence

In comparison to the other methods enumerated just previously, exercise is a very
attractive intervention for a number of reasons (92). Exercise is non-invasive, and
exercise may be conducted in many different types of environments. In addition,
exercise has important health benefits for many other chronic diseases including
arthritis, heart disease, stroke, peripheral vascular disease, diabetes, osteoporosis,
and pulmonary disease (12).
Studies exploring the potential role of exercise in amelioration of
immunosenescence have only recently been initiated. Several reviews have been
previously published reviewing the potential effects of exercise on immunosenes-
cence (27, 147, 170, 171, 214-216, 238, 247). However, a recent expansion of
research on this topic has necessitated a re-assessment of the current literature.

Immune Response to Single Bouts of Exercise
Some researchers have concluded that immune response to acute exercise in eld-
ers is maintained with age (183) whereas others contend that it is similar but
reduced in elders (37). As single bouts of exercise are not expected to reverse
immunosenescence, we will consider here their effects on immune function only
fleetingly, combining data from both human and mouse studies. In general, older
adults still demonstrate immunoresponsiveness to a single bout of exercise,
although the magnitude of this response is smaller compared with young controls
(149). Acute exercise in older subjects is known to increase NK cell activity (41,
227) and circulating numbers of neutrophils (30, 32); potentially increase second-
ary antibody response to booster injections (115); change circulating T cell popu-
lations (37, 149) and induce leukocytosis (26, 37); and modulate T cell prolifera-
tion (37, 45, 149).

Long-term exercise and immune function (Human Studies)
Cross Sectional studies
Several cross sectional studies have evaluated immune responsiveness in older
adults who regularly participate in exercise compared to those who remain seden-
tary. The impact of physical activity on NK cell function in older adults is not
clear. NK cell cytotoxicity of K562 tumour targets is thought to be maintained
with ageing, although there may be some decline of NK activity on a per cell
basis (220). In one study, competitive female athletes over 65 years of age
demonstrated higher NKCA (natural killer cell activity) than sedentary controls

16 • Immunosenescence and exercise

(171). Shinkai et al. (214) evaluated NKCA in elderly runners and did not find a
significant difference between runners and controls. However, in a follow-up
study, a slightly greater NKCA on a per cell basis was found in 50-59 year old
runners compared to controls (216). Recently, it has also been shown that the con-
centration of CD16+CD56+ NK cells was greater in elderly subjects (over 60
years of age) that exercised on a regular basis in comparison to age-matched con-
trols (249). Together, these studies suggest that exercise may slightly enhance
NKCA in older adults, although additional studies are needed to confirm this pos-
sibility. There is minimal data regarding the effects of physical activity on other
innate defences in humans. One group has shown that the age-associated decline
in neutrophil phagocytic function is attenuated by exercise in adults aged over 60
(249), yet further research in this area is needed.
The influence of exercise participation on T cell proliferation in response to
mitogens has also been evaluated. Greater lymphocyte proliferation in response to
the mitogens phytohemagglutinin (PHA) and pokeweed mitogen (PWM) has
been reported in older recreational male runners compared to controls (214, 216).
Similar findings were reported with respect to PHA-induced lymphocyte prolifer-
ation in older competitive females athletes (171). Another T cell functional meas-
ure, the expression of CD25 (IL-2a receptor) may decline with advancing age (79,
237). One study observed that T cells from active older women showed a greater
CD25 expression on T cells compared to less active. T cell signal transduction
involving protein kinase C (PKC) has also been reported to decline with age
(242). To investigate whether age-related changes in lymphocyte protein kinase
C (PKC) activity may play a role in immunosenescence, one team studied PKC
activity from both cytosolic and membranous fractions of lymphocytes isolated
from older men and compared basal or stimulated (with PHA or phorbol myristate
acetate [PMA]) activity. They found that older men had consistently lower PKC
activity levels across all cellular locations and stimulation schemes, but that indi-
viduals who exercised regularly had a lesser magnitude of reduction as compared
to the younger controls (240).
Three recent studies have evaluated the effects of physical fitness on the
immune response to antigens in vivo. These models may have greater physiologi-
cal relevance than mitogen-induced stimulation of PBMC in vitro, because the in
vivo measures of immunity evaluate the antigen-specific response, similar to actu-
al challenge with a pathogen. In one such study, older adults that regularly per-
formed aerobic exercise produced greater amounts of anti-influenza IgG and IgM
two weeks post-immunization compared to less active or sedentary individuals
(125). In this same study, lymphocyte proliferation to influenza antigen was
greater in the participants reporting either regular activity or less intense activity
compared to sedentary individuals. In a similar study, physical activity was
assessed using the Physical Activity Scale for the Elderly (PASE), and antibody
titre was measured in response to influenza immunization (206). At one-week
post-immunization, the antibody titre was significantly correlated with the level
of physical activity, although this correlation was not observed at 2, 4, or 6 weeks
post-immunization, suggesting that exercise may alter the kinetics of immune
response. The primary response to a novel antigen, keyhole-limpet hemocyanin
(KLH), was recently assessed in young and old, active and inactive adults (219).
With respect to anti-KLH antibody, IgM, IgG, IgG1, but not IgG2 were signifi-

Immunosenescence and exercise • 17

cantly greater in the older active adults compared with the sedentary older adults.
The delayed type hypersensitivity (DTH) response to KLH was also measured in
this study, reflecting the ability of T cells to proliferate and migrate in response to
antigen. Again, exercise was associated with an improved DTH response. Taken
together, these studies suggest that immune response to antigen challenge may be
improved in older adults. In these studies, both, measures of B cell function (anti-
body), and T cell function (proliferation, DTH) were enhanced in the older adults
that exercise regularly, perhaps providing greater protection from infection.

Prospective studies
Several prospective studies have compared infection history over a period of time,
and only a few exercise intervention trials have been performed in older adults.
Based on the published studies, the effects of exercise training as means of revers-
ing immunosenescence are variable. However, it appears that long-term (> 6
months) interventions show the greatest promise. For example, in four of five inter-
vention studies > 6 months duration, improvements of immune function were
observed (2, 53, 117, 123, 244). In contrast, the findings from six of seven studies
that involved shorter-term interventions were not promising in terms of enhanced
immunity (17, 39, 41, 70, 73, 171, 194, 199). Therefore, unlike some physiological
parameters such as the maximal oxygen uptake that improve in 8-12 weeks, a
longer period of time may be necessary before adaptations in immune function
occur. A comparison of the immunomodulatory effects of different types of exercise
interventions or physical activity patterns over time is presented in the next section.

The influence of physical activity on risk of developing an infection in older
adults has been examined in several studies. The risk of hospitalization for infec-
tious disease was examined in 1,365 women aged 55 to 80 years. In this study,
physical inactivity was associated with increased risk of infection (adj. odds
ration = 4.08; 95% CI, 1.73-9.63) (136). Similarly, in a separate investigation, the
total number of upper respiratory tract infections (URTI) and total number of days
with URTI symptoms over a 12-month period was significantly negatively associ-
ated with daily energy expenditure in sports activity among older adults (129).
Recently, the risk of developing physician-diagnosed community acquired pneu-
monia was evaluated in a large study population that included adults up to age 79
(8). Again, the risk of developing pneumonia decreased with increasing levels of
physical activity, but only among women. In an aerobic exercise intervention trial
of 12 weeks duration, elderly women assigned to a 5 days/week, 30-40 minutes at
60% of heart rate reserve, had a significantly lower incidence of upper respiratory
tract infection as compared to a calisthenic (light flexibility) program (171).
Recent data from our laboratory also suggested that over the course of a 10-month
aerobic exercise intervention (3 days/week, 25-30 minutes at 65-75% of heart rate
reserve) that began in November, participants assigned to the exercise group
experienced fewer days of URTI symptoms compared to sedentary control sub-
jects, although the n was small (n=14 exercise, n=14 control; Figure 1, Kohut et
al., unpublished observations). The evidence from these prospective studies gen-
erally suggests that greater levels of physical activity are associated with reduced
risk of infection. The causal link between exercise and infection remains to be

18 • Immunosenescence and exercise

Immunosenescence and exercise • 19

determined, however,
recent studies suggest
that exercise may attenu-
ate immune decline
associated with ageing.

Natural Killer cell func-
The effects of exercise
training on NK cell
activity were examined
in several studies,
although the findings
from some studies have
suggested that total
Figure 1. The total number of reported upper respiratory NKCA is not affected to
tract infections was compared between aerobic exercise and a large extent by the age-
control subjects over the 10-month intervention period. No ing process. In the study
difference existed between groups. The total number of days by Woods et al. (244), a
with URTI symptoms was also compared between groups trend towards increased
during this same time period. The exercise subjects reported NKCA was observed in
significantly fewer days with symptoms (p=0.031). Note, ill- subjects completing a 6-
ness were not physician verified and the n was small (n=14 month aerobic exercise
intervention. Sixteen
control, n=14 exercise).
weeks of training with
chair callisthenic exercise was also associated with increased NKCA, although no
pre-intervention measures were made, thus limiting the findings from this study
(41). In contrast, a twelve week aerobic exercise program, a 10-week aerobic
exercise intervention, and a 10-week resistance training program did not improve
NKCA (70, 73, 171). NKCA actually declined in frail older adults following 3
months of exercise in comparison to a control group (199). In summary, the
impact of exercise training on NKCA in older adults is not clear, with shorter term
interventions showing no change and longer term interventions suggesting a
slight increase in function. In future studies, it would be worthwhile to determine
if a specific time period of exercise training is necessary before changes are
observed in NK function, and whether certain aspects of NK function thought to
change with ageing (e.g., response to interferonα or IL-2) may be modified by
exercise (21, 246).

T lymphocyte responses and related cytokines
The role of exercise training on several aspects of T cell function have been eval-
uated in older adults including T lymphocyte proliferation, cytotoxic T cell func-
tion, expression of activation and costimulatory markers, delayed type hypersen-
sitivity, and cytokines (IL-2, IL-4, IFNγ). Numerous studies have demonstrated
that ageing is associated with decreased T cell proliferation (55), impaired CTL
function (190), reduced expression of the costimulatory molecule CD28 (56),
diminished expression of the activation markers CD25 and CD69 (79, 205), and a
large decline in IL-2 production (54, 229). This age-related dysfunction in the T

cell has been theorized to play a major role in altering general immune function
including those associated with earlier mortality (178). The evidence to date has
suggested that longer-term interventions appear to have a greater effect on T cell
function than short-term exercise interventions. T cell proliferation to mitogen
tended to increase following a 6-month aerobic exercise intervention (244),
increased significantly following 10 months of aerobic exercise (134), but did not
change after 12 weeks of similar exercise (171). In contrast, resistance training
for 10-12 weeks did not alter proliferation to mitogens (73, 194). It is also of
interest to note that a 32-week intervention involving endurance and strength
exercises did not change proliferation among frail elderly adults (117).
A measure of T cell-mediated response in vivo, the DTH response, did not
increase after either a 12-week resistance program (194) or a 17-week exercise
program (39), although there were some concerns with the methods used to meas-
ure DTH in the second study. The effect of a longer term aerobic exercise inter-
vention on DTH response in older adults has not yet been published, to our
Cytotoxic T cell function has been shown to be essential in viral clearance,
and we are aware of only one investigation that has examined CTL response to
viral challenge among older adults. Following 10 months of aerobic exercise, the
CTL response as assessed by Granzyme B, was greater among exercisers com-
pared to control subjects for 2 of 3 antigens contained in the influenza vaccine
(123). Given that the CTL response to influenza virus was impaired among older
adults (192), an improvement in CTL function may have clinical benefits.
Cytokine production by T cells has also been reported to change with age-
ing, and the decline in IL-2 production has been well-documented. A recent study
showed that the percentage of lymphocytes expressing intracellular IL-2 was
greater in elderly women (aged 62-86) that attended an aerobic exercise program
for 2 years as compared to sedentary women (53). However, the authors found no
difference between exercise and control subjects with respect to the percentage of
lymphocytes expressing intracellular IL-4 or IFNγ in response to PMA and calci-
um ionophore. One limitation to this study was the lack of baseline pre-interven-
tion immune measures between the groups.
Other measures of T cell responsiveness have included the expression of
CD25 (IL-2 receptorα), HLA-DR (component of Class II major histocompatibility
molecules), and expression of the costimulatory molecule CD28. In the only pub-
lished study to examine the effects of exercise on these T cell activation markers,
no benefits of a 32-week endurance and strength training program were found in
frail elderly subjects (116). In a separate study, 10 months of aerobic exercise or
flexibility/resistance exercise did not alter expression of the early T cell activation
marker, CD69 (134). However, data from the same laboratory did show that the
10-month aerobic intervention significantly increased CD25 expression, whereas
10 months of flexibility and resistance training did not alter CD25 expression (Fig-
ure 2; unpublished results, Lee et al). To our knowledge, this was the first data to
compare immune responses associated with a long-term aerobic exercise interven-
tion in contrast to a long-term resistance/flexibility exercise intervention.
Taken together, the results from several studies indicated that long term aer-
obic exercise interventions improved T cell responses among older adults.
Although resistance training did not appear to improve T cell function, the dura-

20 • Immunosenescence and exercise

tion of the intervention
was shorter (10-12
weeks), and aerobic
exercise trials of a simi-
lar duration also did not
increase T cell response
in older adults (171).
The only data that we
are aware that evaluated
a longer term resistance
exercise intervention is
shown in Figure 2, and
fewer benefits were
Figure 2. After a 10-month intervention, the percentage of found with resistance
CD25+ expressing cells was significantly greater (p=0.042) training compared to
among the participants of the aerobic intervention as com- aerobic exercise. Addi-
pared to the strength/flexibility intervention. Baseline tional studies regarding
the role of resistance
CD25+ values were used as a covariate in the analysis.
exercise would be
informative. Another concern from current data was that the potential improve-
ments of T cell function associated with aerobic exercise may not apply to frail,
older adults. The two studies that included this population failed to observe sig-
nificant improvements of T cell function after 17 weeks or 32 weeks of training
(39, 117). Longer periods of exercise training may have been required before
effects may be seen in this population or it may be that frail older adults may not
be capable of exercising at a sufficient intensity to elicit changes of immune com-
petence. Although the data has been very limited, in a comparison of lower inten-
sity exercise with moderate/vigorous intensity exercise, immune benefits were
observed only in the subjects participating in higher intensity exercise (125).
Alternatively, it is possible that older adults who may be classified as suffering
from frailty syndrome, have reached a stage at which it is not possible to reverse
age-related declines of immune function. In summary, the data from exercise
intervention trials among older adults suggests that aerobic exercise may enhance
T lymphocyte responses, but longer periods of exercise are likely required before
benefits are observed, and benefits may not be found in all populations.

The effects of exercise training on antibody responses have been evaluated in two
studies. In one of these studies, salivary secretory IgA levels were evaluated after
12 months of endurance and resistance training (2). The prevalence of mucosal
infections appears to increase with age, and IgA on mucosal surfaces may act as
one of the first lines of defence against infection. However, several studies have
shown that salivary IgA concentration and secretion rates tended to increase with
age (5, 38, 71) including IgA antibodies to specific microorganisms (185),
although there was one report of diminished salivary IgA secretion rate (157).
Interestingly, exercise training (60 minutes aerobic and 60 minutes resistance
training per week for 12 months) was associated with an enhancement of both
salivary IgA concentration and secretion rate (2). Presumably, the exercise-

Immunosenescence and exercise • 21

induced increase would be associated with greater protection from mucosal
microbial pathogens, although this remains to be established.
A significant number of older adults do not develop a protective antibody
titre following immunization with influenza vaccine, leaving these individuals
potentially vulnerable to infection (120). Another recent study evaluated the
effects of exercise training on serum antibody titre to influenza vaccine. In an
exercise trial, older adults participated in a 10-month aerobic exercise interven-
tion, and antibody titre in response to influenza vaccine was measured. At base-
line, prior to the intervention, there was no difference in antibody titre between
the exercise and control group. In contrast, after the exercise intervention, the
exercisers responded to the annual influenza vaccine with a greater increase in
antibody titre than the control group (123). Although the antibody titre among
exercisers increased to a greater extent than the control subjects, the level among
elderly exercisers did not reach the titre in a young comparison group. This sug-
gests that exercise may attenuate, rather than completely reverse immunosenes-
cence. This study may have important clinical implications given that protection
from influenza infection has been correlated with higher serum antibody titre (91)
and therefore, even a slight improvement in antibody response could potentially
result in better protection from infection.

Inflammation and Pro-inflammatory cytokines (IL-1β, TNFα, IL-6, IL-18)
Due to the limited information on the topic of inflammation, both cross sectional
and prospective studies have been included in this section. In recent years,
inflammation and markers of inflammation have been associated with a number
of chronic diseases; for recent reviews see (78, 130, 231). In particular, elevated
inflammatory cytokines and inflammatory factors such as C-reactive protein
(CRP) have been associated with, or implicated in the pathogenesis of: osteoporo-
sis (146), diabetes (193), cardiovascular disease including atherosclerosis (19, 28,
72, 108), obesity (42), hypertension (10), frailty, disability and mortality (33, 64).
An increase in monocyte production of inflammatory cytokines has been reported
with advancing age (198, 203). Several epidemiological studies have suggested
that exercise may minimize inflammation. For example, the NHANES III data
that included 13,738 subjects showed that the odds ratios for elevated CRP were
reduced to 0.85 (95% confidence interval 0.70-1.02) for those adults participating
in moderate activity, and further reduced to 0.53 (CI 0.40-0.71) for those partici-
pating in vigorous physical activity (75), after adjusting for many factor including
body mass index (BMI). In a smaller study, however, the inverse association
between inflammatory factors and physical activity was no longer significant
after adjusting for BMI (188). In a study focused on middle-aged and older
adults, greater levels of physical activity were inversely related to CRP levels
(odds ratio 0.63; 95% CI 0.43-0.93) for those participating in physical activity >
22 times per month (1). The one study that examined only those adults > 65 years
of age also observed that participants in the highest quartile of physical activity
had 19% lower concentrations of CRP than those in the lowest quartile of physi-
cal activity, after adjusting for disease and BMI. The epidemiological data gener-
ally supports the possibility that regular exercise may reduce levels of inflamma-
tory mediators, and although the mechanism remains to be determined, it has
been suggested that muscle derived IL-6 may play a role (182).

22 • Immunosenescence and exercise

Several prospec-
tive studies have evalu-
ated the impact of exer-
cise training on inflam-
matory cytokines or
mediators. A 10-week
resistance training pro-
gram in older women
reduced the levels of IL-
6, TNF-α, IL-1β pro-
duced by LPS-stimulat-
ed peripheral blood
mononuclear cells (187).
Similarly, a 3-month
Figure 3a. The level of serum IL-6 tended to decline in the resistance exercise inter-
cardio group as compared to subjects in the strength/flexibil- vention among frail eld-
ity training group. A statistical trend towards a greater erly participants de-
decrease in the cardio compared to the strength/flex group creased TNF-α mRNA,
was observed (p=0.10); n=19 cardio subject, n=19 although in this study,
the TNF-α was meas-
strength/flex subjects.
ured in muscle tissue.
The authors suggested that resistance training may attenuate muscle wasting
associated with advancing age, given that elevated TNF-α may be related to
muscle wasting (66). A separate study of frail older adults evaluated both nutri-
tional and exercise interventions in a 17-week randomized trial. In a subgroup
of subjects who had detectable levels of serum CRP, it appeared that exercise
reduced CRP by 1.3 + 1.2 mg/L, and the combined exercise/nutrition interven-
tion decreased CRP by 8.5 + 17.0 mg/L (44). However, the number of subjects
was low and the results are of questionable statistical significance. Flynn et al.
(74), took an interesting approach in an experiment designed to examine the
effects of resistance training on toll-like receptor 4 and CD14 mRNA expres-
sion in elderly women. Toll-like receptor 4 and CD14 are involved in signal
transduction in response to bacterial LPS, resulting in the release of pro-inflam-
matory cytokines. After a 10-week resistance training intervention, the mono-
cytes from the exercise participants demonstrated reduced Toll-like receptor 4
and CD14 mRNA expression. However, exercise was not associated with
changes in IL-6, IL-1β, or TNF-α mRNA per leukocyte. Although this study is
somewhat complicated by the inclusion of subjects taking different hormone
replacement therapies or other medication in the exercise group compared to
the control group, and the lack of pre-intervention measures, this is the first
attempt to assess the potential effects of exercise on receptors important in LPS
signaling in association with pro-inflammatory cytokines. In the only published
trial that we are aware of that evaluated long-term exercise and pro-inflammato-
ry cytokines, slightly younger participants were studied (women mean age 49.7,
men mean age 48.1) (218). The cytokines were measured using peripheral
blood mononuclear cells with or without the mitogen PHA. The production of
the inflammatory cytokines IL-1α, TNFα, IFNγ decreased after a 6-month exer-
cise intervention, whereas the production of the “atheroprotective” anti-inflam-

Immunosenescence and exercise • 23

matory cytokines IL-10,
IL-4, TGFβ increased in
both PHA-stimulated
and non-stimulated cell
cultures. These results
were promising, but
need to be evaluated
among older adults.
Also, it is important to
note that many of the
studies linking pro-
inflammatory cytokines
and chronic disease
have evaluated serum
Figure 3b. The level of serum CRP tended to decline in the levels of these cytoki-
cardio group as compared to subjects in the strength/flexibil- nes, rather than cytoki-
ity training group. A statistical trend towards a greater nes produced by periph-
decrease in the cardio compared to the strength/flex group eral blood mononuclear
was observed (p=0.09); n=18 cardio subject, n=20 cells. Our laboratory
has recently examined
strength/flex subjects
the effects of long-term
(10-month) exercise interventions on serum levels of IL-6 and CRP using high
sensitivity ELISA kits. A resistance/flexibility program was compared with a
cardiovascular exercise intervention. Both groups exercised 3 times per week,
with the cardiovascular group exercising at 65-75% of heart rate reserve for 25-
30 minutes per session whereas the resistance/flexibility group performed flexi-
bility exercises and 1-2 sets of resistance exercises (8-15 reps/set). The results
are shown in Figure 3a. Serum IL-6 tended to decrease in the subjects that par-
ticipated in the cardiovascular intervention, whereas no change occurred in the
resistance training group (change from pre-intervention, p=0.10). Figure 3b
shows a similar pattern with respect to serum CRP, a trend towards a decrease
in the serum of cardiovascular subjects, but no change in the strength/flexibility
trained subjects after the intervention (p=0.09).
The research focus on pro-inflammatory cytokines/ inflammatory mediators
and their potential role in chronic disease is relatively new. The effects of acute
exercise on inflammatory cytokines have been investigated in numerous studies
ever since the first innovative work published by Cannon and Kluger in 1983
(31). However, it is not known whether chronic exercise can minimize the
“inflammatory state” associated with many chronic diseases. Perhaps the mecha-
nism by which exercise training minimizes the risk of developing chronic condi-
tions such as heart disease or diabetes, involves a reduction in the inflammatory
cytokines. This field of research will be improved by additional long term studies
that simultaneously evaluate the influence of exercise rehabilitation on pro-
inflammtory mediators and the risk of developing chronic conditions including
frailty, as well as overall mortality.

Animal studies
There are numerous animal studies that have evaluated the role of exercise as an

24 • Immunosenescence and exercise

immunomodulator, and some of these investigations have examined the incidence
or severity of infection. This review will focus primarily on studies that used aged
animal models and present data on the question of whether exercise can attenuate

T cell proliferation and IL-2 in response to mitogens
T lymphocyte responses, particularly proliferation and IL-2 production are
reduced with advancing age, both in animal models as well as humans. Both rats
and mice have been used to evaluate the effects of exercise training on T lympho-
cyte function and the results are variable. For example 6 months of swim training
in rats actually reduced proliferation and IL-2 production in young rats (7
months), however, there appeared to be no difference in these same immune
parameters comparing exercise and sedentary older rates (18 months) (176). Two
other studies that used running as the exercise mode found that 15 weeks of exer-
cise training increased ConA-induced proliferation in rats 27 months of age, and
that 21 months of daily exercise resulted in a trend towards increased prolifera-
tion to PHA in rats 23 months of age which became statistically significant if high
and low responders were evaluated separately (167, 236). Interestingly, prolifera-
tion decreased in young (8 months) and middle aged (17 months) rats exposed to
the same 15 week exercise regimen (167). A similar pattern was seen with respect
to ConA-induced IL-2 such that 15 weeks of exercise improved IL-2 production
in the older rats (27 months) but IL-2 declined in young or middle aged rats. The
differences in age in those rats defined as old (18 months as compared to 23 or 27
months) may account for the seemingly different findings. The middle-aged rats
(17 months) that also showed a decline in proliferation with exercise training in
the treadmill running study were nearly the same age as the “old” rats in the pre-
vious swim training study that showed no difference in proliferation. Contrasting
results were reported in a recent study that evaluated 8 weeks of treadmill running
using young (4 months) and older (18 months) mice. The investigators found that
exercise training was associated with decreased proliferative response to ConA or
PHA in older mice, but the opposite was true in young mice (increased prolifera-
tion to PHA, but not ConA) (127). It is currently difficult to draw a conclusion
regarding the role of exercise training in reversing the age-related decline in mito-
gen-induced proliferation, based on the current data in animal models.

Infection models and TH1 / TH2 cytokines
An 8-week treadmill exercise program (5 days/week, 45 minutes/session), fol-
lowed by exposure to intranasal exposure to HSV-1 virus was used to determine
whether the production of virus-specific cytokines was affected by exercise in
young (4 month) and old (18 month) mice (127). Immune responses were meas-
ured 10 days post-infection, by culturing spleen cells with the same virus in vitro
to elicit virus-specific responses. In young mice, IL-2 was enhanced by exercise,
and in old mice the kinetics of IL-2 production appeared be changed by exercise,
rather than total IL-2. In a similar study from the same group of investigators,
immune responses were evaluated at 7 days post-infection. IL-2 was significantly
increased among old exercised mice, and showed a trend towards an increase in
young mice (124). Another TH1 cytokine important in viral infections is interfer-
on gamma (IFNγ). In these same experiments, the IFN-γ responses were very

Immunosenescence and exercise • 25

similar to IL-2 (old mice – significant increase 7 days post and altered kinetics at
10 days post; young mice – trend to increased 7 days post and significant increase
at day 10 post). The TH2 cytokine, IL-10 was also studied in the viral infection
model. At 7 days post-infection, a slight trend towards increased IL-10 was
observed in both age groups in exercised mice, whereas by 10 days post-infec-
tion, exercise significantly increased IL-10 in both young and old mice. Taken
together, these findings suggested that exercise training may enhance TH1
cytokines earlier during infection, but affect TH2 cytokines later in the course of
infection. With advancing age, it has been suggested that there is a shift in the
TH1/ TH2 cytokine balance, particularly with a decline in the TH1 cytokines (81).
The possibility that this shift in cytokine balance may contribute to an increased
rate of infections has been raised (210). Perhaps exercise reduce infection severi-
ty among aged populations by altering the TH1/ TH2 balance early in the course of
infection, yet the data to support this possibility are currently very limited.

Macrophage function
Age-associated declines in macrophage function may be reversed by exercise.
One study showed that moderate, regular exercise (5 days/week, 45 minutes/day,
16 weeks) in older mice increased the capacity of peritoneal macrophages to kill
tumour cells in vitro (142).

Furthermore, the results indicated that nitric oxide
appeared to be responsible for the exercise-induced increase in macrophage anti-
tumor function. In a separate study of older mice, exercise training (5 days/week,
45 minutes/day, 9 weeks) reversed the age-related decline in the LPS/IFN-γ-stim-
ulated production of TNF-α by peritoneal macrophages (126). Interestingly, the
investigators also observed that ageing was accompanied by an increase in alveo-
lar macrophage LPS/IFN-γ-stimulated production of IL-12, and exercise training
reduced IL-12 in older mice, similar to the response of younger mice. Peritoneal
macrophage antiviral resistance to HSV-1 also appeared to increase with age. The
same 9-week exercise protocol further enhanced macrophage antiviral resistance
in older mice. In a separate study from the same group, ageing was associated
with increased IL-12 production in spleen and alveolar cells (124). Exercise tend-
ed to decrease LPS/IFN-γ-stimulated IL-12 in both young and old mice, although
this did not quite meet statistical significance (p=0.063). Although more studies
of exercise and its effects on macrophages from the aged are needed, these initial
studies show some promise in reversing some of the age-related alterations of
macrophage function.

Three studies have evaluated the role of exercise training on antibody production
in aged animals. In an earlier study of rats, trained for 10 weeks with treadmill
running, there was no change in the antibody response to KLH in the exercised
compared to control rats (11). In two studies involving 8 weeks of treadmill exer-
cise in aged (18 months) and young mice (4 months), IgM antibody to HSV-1
virus was not increased by exercise 7 days post-infection (124), but did appear to
be enhanced by exercise in both young and old mice at 10 days post-infection
(127). Again, the timing of antibody measure in relation to antigen challenge may
influence the effects of exercise. Also, antibody titre without some measure of
infection severity may be difficult to interpret.

The naïve/memory T cell ratio has been shown in numerous human and animal
models to change with age, with a decline in naïve cells and an increase in memory
cells. It has been suggested that the decline of naïve cells may impair the ability to
response to novel antigens. Recently, Woods et al. (245) demonstrated that 4
months of exercise training significantly increased the percentage of both CD4+
and CD8+ naïve cells in old, but not young mice. Also, it appeared that the number
of memory cells decreased, but the number of naïve cells did not change. Similar
findings were observed after 8 weeks of moderate exercise in a different study, with
the results suggesting a trend (p=0.07) towards a decline in the percentage of mem-
ory cells found only in older mice . This initial data in animal models is prom-
ising. It remains to be seen whether the same effects may be found in humans. Also,
identifying the mechanisms that drive this change in the naïve/memory cell ratio is
another important objective of future research in this field.

Mechanisms by which exercise may alter immunosenescence
The mechanisms responsible for enhanced immune response resulting from long-
term exercise training have not been elucidated. It has been suggested that neu-
roendocrine factors may be one of these mechanisms . One
approach used to evaluate potential mechanisms relies on pharmacological block-
ade of specific neuroendocrine factors to determine their role in immunomodula-
tion. Relatively few studies have used this approach to examine exercise training-
induced changes (in contrast to acute exercise). With this approach, opioid pep-
tides and catacholamines via beta-adrenergic receptors, have been shown to con-
tribute to the exercise training-induced modulation of immunity .

To our knowledge, there is only one published study that has used pharma-
cological manipulation to study the potential neuroendocrine mediators in the
aged . The findings from this study suggested that beta-adrenergic receptor
activation played a role in modulating antibody, mitogen-induced proliferation,
and TH1 cytokines (IL-2, IFN-γ), but not the TH2 cytokine, IL-10. However, the
role of beta-adrenergic receptors appeared to be age-dependent, because beta-
adrenergic blockade in young mice did not appear to mediate the exercise-induced

Immunosenescence and exercise

Ageing may be accompanied by an alteration in the TH1/ TH2 cytokine balance,
particularly a decline in IL-2, and exercise appears to improve both IL-2 produc-
tion and IL-2 receptor expression. Although these limited results are promising,
further research is clearly needed. The mechanisms that underlie the exercise-
mediated immunomodulatory effects are unexplored, with only one study sug-
gesting a role for beta-adrenergic receptors. Many aspects of immune function
remain to be further examined including dendritic cells, antigen processing and
presentation, cell signaling events, costimulatory molecules, response to infec-
tious challenge including immunopathology, etc. Clearly, this is a new and grow-
ing area of research, with substantial public health significance.


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Overall, the combined data suggest that exercise may be an efficacious therapy
for partially restoring immune function in geriatric populations, particularly when
long-term exercise interventions are employed. Currently, there are insufficient
data to determine: 1) whether aerobic exercise has different effects than resistance
training, 2) an optimal amount of exercise that can be recommended, and 3) if the
benefits of exercise are restricted to certain populations.
The results from the studies presented suggest that exercise may reverse
several characteristics of immunosenecence. A reversal of the age-related decline
in the naïve/memory cell ratio may contribute to an impaired response to new
antigens, and data suggests that exercise influence the naïve/memory ratio. Also,
the age-related decline in vaccine efficacy due to reduced antibody may be
improved by exercise, as well as the T-cell and B cell response to novel antigens.


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