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Age-associated increase in oxidative stress and nuclear factor B activation are attenuated in rat liver by regular exercise¹

ZSOLT RADÁK^*,2, HAE YOUNG CHUNG^,2, HISASHI NAITO, RYOYA TAKAHASHI, KYUNG JIN JUNG, HYON-JEEN KIM and SATARO GOTO

^* Laboratory of Exercise Physiology, School of Sport Science, Semmelweis University, Budapest, Hungary;
Department of Pharmacy, Pusan National University, Pusan, Korea;
Department of Sports Physiology, School of Sports Sciences, Juntendo University, Tokyo, Japan; and
Departiment of Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan

² Correspondence to: E-mail: radak{at}mail.hupe.hu or hyjung{at}pusan.ac.kr

SPECIFIC AIMS

The oxidative stress theory argues that senescent phenotypes (i.e.the intrinsic physiological and biochemical decline with age resulting in decreased survival) are primarily due to the accumulation of oxidative damage to cellular components. Environmental interactions that increase the ability of an organism to either decrease the production of ROS or increase the activity and effectiveness of antioxidant systems, have the potential to retard aging and increase average and/or maximal life span. One such environmental intervention that remains equivocal with respect to its effects on ROS production is regular physical exercise.

Nuclear factor B (NF-B) is a redox-sensitive and oxidant-activated transcription factor which regulates inflammation-related gene expression, viral replication, cell-cell interactions, apoptosis, and proliferation, and is known to be up-regulated with aging. It is not known, however, how regular exercise affects the activity of NF-B in aging animals. In the present investigation, we tested the hypothesis that age-associated increases in ROS production and NF-B activation are attenuated by regular exercise even in old age.

PRINCIPAL FINDINGS

1. Regular exercise decreases the rate of ROS generation and prevents the age-associated shift in redox state
We showed that aging is associated with increased formation of ROS in the liver of 30 month old rats, compared with the 20 month old group as measured by dichlorodihydrofluorescein diacetate probe. The regular treadmill running for 8 weeks which resulted in 40% increase in maximal oxygen uptake, caused down-regulation of ROS production in the liver of trained rats. Exercise-dependent decrease in the ROS levels was confirmed by other oxidative markers. Because increase in GSSG at the expense of GSH is associated with oxidative stress, the change of GSH and GSSG levels was assessed. Although old rats showed almost the same GSH level as adult rats, exercised rats of both age groups had a higher GSH level compared with nonexercised counterparts. Thus, regular exercise upregulates cellular antioxidant capacity in the liver even in old age.

2. Regular exercise prevents the age-associated increase in NF-kB signal transduction pathway
To inquire into the exercise-related activation of NF-B, elecrophoretic mobility shift assay (EMSA) was performed with nuclear proteins. Figure 1 illustrates that aging is associated with an increase in the nuclear binding activity of NF-B and the increase was attenuated by regular exercise. The data conclusively demonstrated that aging causes NF-B activation, while regular exercise attenuates the age-related increase in NF-B activity.

View larger version (56K): [in this window] [in a new window]   Figure 1. Regular exercise suppresses age-related increase in NF-B activity. EMSA was used to compare nuclear NF-B binding activities in liver nuclear proteins from adult and old rats correlating with exercised animals. One representative result is shown from three experiments that yielded similar results (A). The level of NF-B DNA binding was quantified by densitometry (B). The data shown are presented as arbitrary value of the density. AC, adult contol; AT, adult exercise; OC, old contol; OT: old exercise. Statistical significance. a, P < 0.001, adult compared with old, b, P < 0.001 between age-matched control and exercised groups.

Dissociation of cytosolic I-B from NF-B/I-B complex is known to play a crutial role in the translocation of NF-B into the nucleus, the I-B being degraded upon phosphorylation in many but not all situations of stress. As ascertained by the present study, the I-B level in the cytosol decreased with age in nonexercised groups, while the level in old exercised groups remained higher than that in non- exercised groups (Fig. 2 ). The results indicate that attenuation of NF-B activation by exercise is negatively interrelated with the change in the amount of I-B.

View larger version (33K): [in this window] [in a new window]   Figure 2. Regular exercise prevents age-related degradation of I-B. Western blot analysis was performed to detect hepatic I-B in the cytosol from adult and old rats. Blots were quantified by densitometry. Data shown are presented as arbitrary value of the density. AC, adult contol; AT, adult exercise; OC, old contol; OT, old exercise. Statistical significance. a, P < 0.001, adult compared with old; b, P < 0.001, between age-matched control and exercised groups.

To substantially confirm whether the decrease in I-B protein is associated with the increased nuclear translocation of NF-B, we examined the nuclear protein levels of p50 and p65, components of NF-B, by immunoblot using corresponding antibodies. Results demonstrated that the nuclear p50 and p65 were modulated by aging and exercise, verifying that the nuclear translocation of NF-B is increased with aging, and the exercise prevents this change. Thus, it was corroborated that exercise-related prevention of translocation of NF-B (i.e., p50 and p65) was caused by inhibition of degradation of I-B.

CONCLUSIONS

The present study confirms that aging is associated with a shift in redox state toward oxidized milieu and demonstrates that regular exercise attenuates the age-related increase in cellular ROS concentration. The chronic shift in cellular redox state might mean significantly reduced ability to cope with oxidative stress, due to the decreased mobility of buffering system that involves thiol systems such as GSH. Moreover, age-related increase in the DNA binding activity of NF-B that should be associated with increased transcription of inflammation related genes was found to be attenuated by exercise training. These results provide a molecular explanation for the beneficial effects of regular exercise, underscoring the importance of this natural elixir (Fig. 3 ).

View larger version (15K): [in this window] [in a new window]   Figure 3. Aging is associated with increased production of ROS, shift in redox milieu, increases in inflammation and deterioration of physiological function resulting in decline in the quality of life. Regular exercise, on the other hand, through the down-regulation of ROS production, normalization of cellular redox milieu, and signaling pathways, is potentially capable of retarding the aging process and maintaining the quality of life in old age.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0509fje; doi: 10.1096/fj.03-0509fje

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This Article Full Text (PDF) All Versions of this Article: 18/6/749 03-0509fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by RADÁK, Z. Articles by GOTO, S. Search for Related Content PubMed PubMed Citation Articles by RADÁK, Z. Articles by GOTO, S.