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Original Research

Open Access


  • Jinhee Woo1,†
  • Kwangha Hwang1,†
  • Yul-Hyo Lee3
  • Hee-Tae Roh1

1Department of Physical Education, College of Arts and Physical Education, Dong-A University, Busan, Korea

2Laboratory of Exercise Physiology, Department of Physical Education, Graduate School, Dong-A University, Busan, Korea

3Department of Taekwondo, Youngsan University, Yangsan-si, Korea

DOI: 10.31083/jomh.v16i4.281 Vol.16,Issue 4,October 2020 pp.133-140

Published: 01 October 2020

*Corresponding Author(s): Hee-Tae Roh E-mail:

† These authors contributed equally.


Background and objective

The purpose of this study was to investigate the effects of regular exercise training on nicotinamide ade-nine dinucleotide/sirtuin 1 (NAD+/SIRT1) signaling protein levels in skeletal muscles of middle-aged and old-aged mice.

Material and methods

Experimental animals were 40 male C57BL/6 mice out of which 20 were 38-week-old (middle-aged) and the other 20 were 58-week-old (aged). They were divided into four groups: middle-aged control (MC), mid-dle-aged exercise (ME), aged control (AC), and aged exercise (AE) groups (n = 10, each group). ME and AE groups performed exercise training five times weekly for 8 weeks using animal treadmill, after which gastrocnemius muscles were excised and analyzed.


After 8 weeks of intervention, protein levels of AMP-activated protein kinase (AMPK), SIRT1, forkhead box protein 1 (FOXO1), and NAD+ levels were significantly lower in AC group than in MC group (p < 0.05). In addition, AMPK, SIRT1, FOXO1, NAD+, and peroxisome proliferator-activated receptor gamma coact-ivator 1-alpha (PGC-1α) levels were significantly higher in ME and AE groups that exercised for 8 weeks than in MC and AC groups that did not exercise (p < 0.05).


These results suggest that aging and exercise training have opposite effects on the NAD+/SIRT1 pathway in gastrocnemius muscles and that exercise training can be effective in up-regulation of the aging-related NAD+/SIRT1 pathway.


aging; AMPK; exercise training; FOXO1; NAD+; PGC-1α; SIRT1

Cite and Share

Jinhee Woo,Kwangha Hwang,Yul-Hyo Lee,Hee-Tae Roh. EFFECTS OF EXERCISE TRAINING ON AGING-RELATED NAD+/SIRT1 PATHWAY IN MIDDLE-AGED AND AGED MICE. Journal of Men's Health. 2020. 16(4);133-140.


1. Mouchiroud L, Houtkooper RH, Auwerx J. NAD+ metabolism: A therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol 2013;48(4):397–408. 38.2013.789479

2. Fang EF, Lautrup S, Hou Y, et al. NAD+ in aging: Molecular mechanisms and translational implica-tions. Trends Mol Med 2017;23(10):899–916.

3. Imai SI, Guarente L. It takes two to tango: NAD+ and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2016;2:16017.

4. Lin YF, Haynes CM. Metabolism and the UPR(mt). Mol Cell 2016;61(5):677–82. https://doi. org/10.1016/j.molcel.2016.02.004

5. Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci 2007;32(1): 12–19.

6. Morales-Alamo D, Calbet JAL. AMPK signal-ing in skeletal muscle during exercise: Role of reactive oxygen and nitrogen species. Free Radic Biol Med 2016;98:68–77. freeradbiomed.2016.01.012

7. Jäger S, Handschin C, St-Pierre J, et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 2007;104(29):12017–22.

8. Fulco M, Sartorelli V. Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tis-sues. Cell Cycle 2008;7(23):3669–79. https://doi. org/10.4161/cc.7.23.7164

9. Lee DH. Sirt1 as a new therapeutic target in metabolic and age-related diseases. Chonnam Med J 2010;46(2): 67–73.

10. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434(7029):113–18.

11. Anderson R, Prolla T. PGC-1alpha in aging and anti- aging interventions. Biochim Biophys Acta 2009; 1790(10):1059–66. 2009.04.005

12. Diaz F, Thomas CK, Garcia S, et al. Mice lacking COX10 in skeletal muscle recapitulate the phe-notype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency. Hum Mol Genet 2005;14(18):2737–48. https://doi. org/10.1093/hmg/ddi307

13. Uddin GM, Youngson NA, Sinclair DA, et al. Head to head comparison of short-term treatment with the NAD(+) precursor nicotinamide mononu-cleotide (NMN) and 6 weeks of exercise in obese female mice. Front Pharmacol 2016;7:258.

14. Anderson RM, Bitterman KJ, Wood JG, et al. Nicotinamide and PNC1 govern lifespan exten-sion by calorie restriction in Saccharomyces cer-evisiae. Nature 2003;423(6936):181–5. https://doi. org/10.1038/nature01578

15. Bouzid MA, Filaire E, McCall A, et al. Radical oxy-gen species, exercise and aging: An update. Sports Med 2015;45(9):1245–61.

16. Nilwik R, Snijders T, Leenders M, et al. The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp Gerontol 2013;48(5):492–8. https://doi. org/10.1016/j.exger.2013.02.012

17. Woo J, Shin KO, Park SY, et al. Effects of exer-cise and diet change on cognition function and synaptic plasticity in high fat diet induced obese rats. Lipids Health Dis 2013;12:144. https://doi. org/10.1186/1476-511X-12-144

18. Ko K, Woo J, Bae JY, et al. Exercise training improves intramuscular triglyceride lipolysis sen-sitivity in high-fat diet induced obese mice. Lipids Health Dis 2018;17(1):81.

19. Woo J, Kang S. Diet change and exercise enhance protein expression of CREB, CRTC 2 and lipoli-tic enzymes in adipocytes of obese mice. Lipids Health Dis 2016;15(1):147.

20. Imai S, Yoshino J. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metab-olism and ageing. Diabetes Obes Metab 2013; 15(Suppl 3):26–33.

21. Haigis MC, Sinclair DA. Mammalian sirtuins: Biological insights and disease relevance. Annu Rev Pathol 2010;5:253–95.

22. Houtkooper RH, Cantó C, Wanders RJ, et al. The secret life of NAD+: An old metabolite con-trolling new metabolic signaling pathways. Endocr Rev 2010;31(2):194–223.

23. Katsyuba E, Mottis A, Zietak M, et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 2018;563(7731):354–9.

24. Ljubicic V, Hood DA. Diminished contrac-tion-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal mus-cle. Aging Cell 2009;8(4):394–404. https://doi. org/10.1111/j.1474-9726.2009.00483.x

25. Kim DH, Park MH, Ha S, et al. Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restric-tion. Aging 2019;11(4):1283–304. https://doi. org/10.18632/aging.101838

26. Winder WW, Thomson DM. Cellular energy sens-ing and signaling by AMP-activated protein kinase. Cell Biochem Biophys 2007;47(3):332–47.

27. Wang Y, Liang Y, Vanhoutte PM. SIRT1 and AMPK in regulating mammalian senescence: A critical review and a working model. FEBS Lett 2011; 585(7):986–94. 2010.11.047

28. Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase – Development of the energy sen-sor concept. J Physiol 2006;574(1):7–15. https://doi. org/10.1113/jphysiol.2006.108944

29. Steinberg GR, Carling D. AMP-activated protein kinase: The current landscape for drug develop-ment. Nat Rev Drug Discov 2019;18(7):527–51.

30. Salminen A, Kaarniranta K. AMP-activated pro-tein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 2012;11(2):230–41. arr.2011.12.005

31. Han X, Tai H, Wang X, et al. AMPK activation pro-tects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation. Aging Cell 2016;15(3):416–27.

32. Cantó C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK and SIRT1 for meta-bolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 2010;11(3):213–19. https://doi. org/10.1016/j.cmet.2010.02.006

33. Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabo-lism. Oncogene 2008;27(16):2320–36. https://doi. org/10.1038/onc.2008.25

34. Handschin C, Spiegelman BM. Peroxisome pro-liferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabo-lism. Endocr Rev 2006;27(7):728–35. https://doi. org/10.1210/er.2006-0037

35. Thirupathi A, da Silva Pieri BL, Queiroz JAMP, et al. Strength training and aerobic exercise alter mito-chondrial parameters in brown adipose tissue and equally reduce body adiposity in aged rats. J Physiol Biochem 2019;75(1):101–8.

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