Dose-Response, 8:73–79, 2010

Formerly Nonlinearity in Biology, Toxicology, and Medicine

Copyright © 2010 University of Massachusetts
ISSN: 1559-3258
DOI: 10.2203/dose-response.09-048.Ji

EXERCISE-INDUCED HORMESIS MAY HELP HEALTHY AGING

Li Li Ji, Jonathan R. Dickman, Chounghun Kang, and Ryan Koenig 䊐 The

Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin –
Madison
䊐 Hormesis plays a critical role in producing some major benefits derived from physical
exercise. However whether these known cellular mechanisms are applicable to ameliorate
age-related deterioration of muscle function is not entirely clear. The present communi-
cation proposes that antioxidant adaptation, the peroxisome proliferator-activated recep-
tor gamma coactivator (PGC)-1α activated mitochondrial biogenesis, and eccentric con-
traction-induced, cytokine-propelled muscle inflammation could be important redox-sen-
sitive pathways by which exercise-induced disturbance in oxidant-antioxidant hemeostasis
may serve as a heretic stimulus to promote adaptations that help healthy aging and
improve the quality of life.

Keywords: aging, exercise, hormesis, muscle, reactive oxygen species,

After decades of intensive research it becomes widely accepted among

scientific community that reactive oxygen species (ROS) play a significant
role in aging. Furthermore, ROS are generated during physical exercise
in both animals and human and increased ROS production can modify
intracellular oxidant-antioxidant homeostasis and possibly aging (Powers
and Jackson 2008). However, while there are still unanswered basic scien-
tific questions, gerontologists and the general public alike are interested
in the implication of exercise in modulating aging, and especially, how
hormesis could be involved in exercise-induced health-promoting bene-
fits. Some of the frequently asked questions are “Why does exercise gen-
erate free radicals and causes oxidative damage, but we are still advised to
exercise more often?” “Does participation in regular exercise extend life
span in human?” “How much exercise is good for the body when one gets
older?” “Do old people who are physically active need to take antioxidant
supplementation?” Answering these questions not only requires under-
standing of the dynamic nature of interactions between oxidants and
antioxidants, but also a multidisciplinary approach to analyze the specif-
ic conditions involved. The term Hormesis has been adopted to explain
how a mild oxidative stress associated with exercise can result in favorable
adaptations that protect the body against more severe stresses and disor-
ders derived from physical stress or other etiological origin (Ji et al.
2009). While some authors have now advocated that “exercise is antioxi-

Address correspondence to Li Li Ji, Ph.D., The Biodyanmics Laboratory, 2000

Observatory Drive, Madison, WI 53706. Tel 608-262-7250, E-mail: [email protected]

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dant” (Gomez-Cabrera et al. 2008), American College of Sports Medicine

is already carrying the slogan “exercise is medicine”. This brief commu-
nication intends to address several topics fundamental to exercise-
induced hormetic effects based on basic research derived from cell biol-
ogy, exercise physiology and free radical chemistry. Every effort has been
made to relate discussions to ‘real world’ problems.

(1) DOES EXERCISE INCREASE LIFE SPAN?

Rodent studies show that rats involved in life-time long voluntary run-
ning had a significant prolongation of average longevity even though they
had greater food intake compared to sedentary rats, but the runners did
not show any increase in maximal life span (Holloszy 1993). There is no
data in human showing that exercise can affect longevity. However, in
human population, morbidity is concentrated in the last two decades of
life, beginning on the average at age 55 and increasing in frequency until
the average age of death at 75 with an increase of approximately two years
in longevity in physically active people as compared to less active people
(Paffenbarger et al. 1993). This at first may seem to add to the health care
problem in that more people would be living longer with chronic illness,
but that is not the case. A longitudinal study noted that disability levels in
a vigorously exercising population remained below that of non-exercisers
and significant increases in disability were delayed by approximately 15
years (Fries 1996). These data indicate that engaging in regular physical
activity would increase the age of onset of chronic illness and shorten the
time between the onset of morbidity and death. This compression of the
period of morbidity as a result of physical exercise would represent a sig-
nificant improvement in the quality of life of the elderly and result in
major reductions in the cost of treating the medical conditions of the eld-
erly. Despite these clear benefits, the adaptive mechanisms involved and
the time period where major protection offered by exercise occurs are
still unclear.

(2) WHY IS EXERCISE AN ANTIOXIDANT AND MEDICINE?

There is clear evidence that an acute bout of heavy exercise generates

sufficient ROS to challenge the body’s antioxidant defense system
(Powers and Jackson 2008). However, a review of literature reveals that we
are not in agreement as to how ROS generation could impact on the
physiological function of muscle and other organs. Some research sug-
gests that exercise-induced ROS could retard muscle energy production
and contractile function, whereas others found ROS are actually required
for optimal performance (Reid 2001). One of the most important find-
ings of free radical chemistry of exercise was that muscle contraction can
activate redox-sensitive signal transduction pathways to stimulate the

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expression of certain gene products that function to restore ROS home-

ostasis (Goodyear et al. 1996, Hollander et al. 2001). The pathways that
are sensitive to ROS include nuclear factor kappa (NF) κB, mitogen-acti-
vated protein kinase (MAPK), and heat shock proteins (HSP)(Allen and
Tresini 2000). Recently, peroxisome proliferator-activated receptor
gamma coactivator (PGC)-1α activated signaling pathway has been added
to the list (Handschin & Spiegelman, 2008). Activation of redox-sensitive
pathways usually results in gene products that would restore intracellular
oxidant-antioxidant hemeostasis and protection from potential oxidative
stress. These products include (1) antioxidant enzymes (e.g. manganese
superoxide dismutase [MnSOD], glutathione peroxidase [GPX], γ-glu-
tamyl cysteine synthetase); (2) transcription factors and co-factors
required for nuclear binding (e.g. c-fos, activating transcription factor
[ATF]-2, PGC-1α); (3) molecules controlling redox status, (e.g. thiore-
doxin, glutathione); and (4) a wide range of proteins that could influ-
ence metabolic status and thus ROS production, such as uncoupling pro-
teins (UCP), enzymes in fatty acid and glucose metabolism, and mito-
chondrial fusion and fission proteins (Ji et al. 2009). Because the above
mentioned effects are “health-promoting”, we support the views that
exercise is indeed an antioxidant and medicine. It has been recently
shown that oral administration of antioxidants and inhibition of intracel-
lular ROS source could adversely affect antioxidant enzyme adaptation,
mitochondrial biogenesis and insulin sensitivity in animal and human
skeletal muscle in response to exercise clearly demonstrating that ROS
play a key role in exercise hormesis (Gomez-Cabrera et al. 2008, Kang et
al. 2009a, Ristow et al. 2009).

(3) DOES PGC-1α-INDUCED MITOCHONDRIAL BIOSYNTHESIS

PREVENTS SARCOPENIA?

Skeletal muscle undergoes loss of mass and functionality with aging,

a process known as sarcopenia (Morley et al. 2001). Despite decades of
intensive research, the mechanisms for sarcopenia and potential clinical
measures for its prevention are still lacking. Recent research reveals that
mitochondria participate in almost all important cellular biological func-
tions such as metabolic trafficking, regulating ROS homeostasis, signal
transduction and apoptosis, and that decreased mitochondrial biosyn-
thesis may underlie the mechanism for sarcopenia (Chan 2006).
Mitochondrial biogenesis is largely controlled by PGC-1α, which (1)
interacts with nuclear respiratory factors (NRF)-1/2 to control nuclear
encoded mitochondrial proteins involved in electron transport chain
(ETC) complexes, metabolic pathways for fatty acid and glucose metabo-
lism, UCP expression and apoptosis, and (2) promotes mitochondrial
transcription factor A (Tfam) expression thus regulating mitochondrial
DNA (mtDNA) replication and gene expression of mtDNA-encoded pro-

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teins (Kelly and Scarpulla 2004). Moreover, mitochondrial morphology

(size, shape and motility) can be regulated by controlled expression of
mitochondrial fusion and fission protein (Chan 2006). Finally, PGC-1 con-
trols most of the enzymes and proteins affecting oxidant-antioxidant bal-
ance such as UCP2/3, MnSOD and GPX expression (St-Pierre et al. 2006).
Several studies have shown that an acute bout of endurance exercise and
stimulated muscle contraction can upregulate PGC-1α and activate mito-
chondrial protein synthesis and proliferation (Baar et al. 2002).
Furthermore, repeated exercise bouts (exercise training) could result in
accumulation of PGC-1α, NRF-1, and Tfam protein levels. These observa-
tions were thought to play an important role in mediating mitochondrial
adaptation to exercise, such as elevated respiratory activity (oxygen con-
sumption), increased expression of Krebs cycle and ETC enzymes, enhanced
fatty acid oxidation and mitochondrial morphological changes. We recently
showed that ROS generation during acute sprinting exercise can activate
PGC-1 pathway and stimulate mitochondrial biosynthesis, because reducing
ROS generation with allopurinol to inhibit xanthine oxidase (XO), the main
ROS source of this type of exercise, attenuated PGC-1α expression and PGC-
1α -controlled signaling pathway (Kang et al. 2009a).
Does aging attenuate PGC-1α-controlled mitochondrial biosynthesis?
Could age-related changes in mitochondrial biosynthesis be a reason for
sarcopenia? These questions still await research in this area (Corton and
Brown-Borg 2005). Our preliminary data indicate that aged (24 mo) rats
had significantly lower gene expression in the PGC-1α signaling path-
ways, shown by decreased mRNA and protein contents for PGC-1α, Tfam
and cytochome c compared to young (4 mo) rats (Kang et al. 2009b).
Furthermore, phosphorylation of the upstream enzymes AMP kinase and
p38 MAPK, as well as cAMP response element (CRE) nuclear binding,
was down-regulated. However, these changes were reversed or partially
prevented by chronic treadmill running for 8 weeks. Thus, exercise train-
ing is a powerful tool to prevent mitochondrial deterioration with aging
and perhaps sarcopenia.

(4) IS MUSCLE INFLAMMATION A REQUIRED PROCESS FOR HORMESIS?

In older people, muscle stretch injury and subsequent inflammatory

response represent a serious threat to health and quality of life.
Weakened muscles are also a main etiological reason for fall, which is the
14th leading cause of death in the United States with annual death rate
increasing by 55% from 1993-2003 among the elderly. Research evidence
up to date suggests that pre-conditioning with eccentric contraction (EC)
is an effective method to improve muscle strength and prevent future
stretch injury (Maruhashi et al., 2007). Thus, eccentric exercise could be
a means to reduce fall and thus decrease mortality in older people.

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Compared to concentric (shortening) contraction, EC causes more

structural damage to the myocyte and oxidative damage to myofibril pro-
teins and enzymes (Reid 2001, Ji et al. 2009). After the initial injury
blood-borne leukocytes (mainly polymorphoneutrophils, PMN) infiltrate
the damaged muscle sites due to the attraction by the adhesion molecules
(e.g. vascular cell adhesion molecule-1 [VCAM-1]) on cell surface.
Subsequently, there is a “respiratory burst” caused by the activation of
NADPH oxidase to generate large amounts of superoxide radicals and
H2O2. There is clear evidence that NFκB and MAPK are activated after
eccentric contraction leading to greater expression of inflammatory
cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1, 6 and
VCAM-1 and escalated ROS production via a vicious cycle. Nevertheless,
this inflammation enhances blood perfusion due to nitric oxide (NO)
production by inducible NO synthase (iNOS), raises temperature to
speed up reactions, and increases hormonal exposure to damaged tis-
sues, all or which are important for healing of damaged tissues. Moreover,
gene expression of antioxidant enzymes are also upregulated so that cells
undamaged by EC, but affected by the PMN infiltration, are more capa-
ble of resisting future indiscriminative attacks. Thus, after the initial
injury and oxidative damage, the muscle not only recovers but also
becomes bigger, stronger and more capable of handling elevated func-
tional demand. However, whether or not old muscles are capable of
responding to hormetic stimulus is still controversial (Ji 2008). It was
recently demonstrated that EC training impairs NFκB activation and over-
expression of inflammation-related genes induced by acute EC in the eld-
erly (Jiménez-Jiménez et al., 2008).
Interestingly, muscle inflammation and subsequent activation of
NFκB could negatively influence the expression of PGC-1α and its effect
on mitochondrial biogenesis. Chronic inhibition of NFκB via the phar-
macological agent pyrolidine dithiocarbamate (PDTC) was found to
increase PGC-1α level suggesting inactivity might down-regulate PGC-1α
due to elevated NFκB activity (Feng et al. 2009). Furthermore, suppres-
sion of NFκB via polyphenols such as curcumin can reduce inflammation
and attenuate muscle atrophy (Alamdari et al. 2009). Handschin and
Spiegelman (2008) recently highlighted the role of PGC-1α as to “control
muscle plasticity, suppress a broad inflammatory response and mediate
the benefits of exercise”.
In conclusion, although exercise does not directly extend life span in
human, it induces several major health benefits such as upregulation of
antioxidant defense, stimulating mitochondrial biogenesis, and preven-
tion of injury. These are important elements for improving muscle health
and reducing sarcopenia, hence delivering clear benefits for healthy
aging.

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