Clinical Oral Investigations

, Volume 23, Issue 3, pp 1397–1405 | Cite as

Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea

  • Ching-Chi LinEmail author
  • Huey-Yuan Wang
  • Shwu-Fang Liaw
  • Chung-Hsin Chiu
  • Mei-Wei Lin
Original Article



The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA.

Materials and methods

Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3 months after MAD.


Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3 months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393–0.748]) to (0.708 [0.533–0.893]) and SIRT1 protein levels in PBMC increased from 0.58 ± 0.23 pg/μg of total protein to 0.95 ± 0.26 pg/μg of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low.


Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC.

Clinical relevance

LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.


Leukocyte telomere length Sirtuin 1 (SIRT1) Mandibular advancement device (MAD) Obstructive sleep apnea Senescence 



We would like to acknowledge the help with statistics from Ms. Fang-Ju Sun of Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.


This work was supported by a grant from the Ministry of Science and Technology (Grant MOST 103-2314-B-303-014-MY2).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consents

Informed consent was obtained from all individual study participants.


  1. 1.
    Lavie L (2003) Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Med Rev 7:35–51CrossRefGoogle Scholar
  2. 2.
    Busse R, Fleming I (1995) Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 27:331–340CrossRefGoogle Scholar
  3. 3.
    Pankow W, Lies A, Lohmann FW (2000) Sleep-disordered breathing and hypertension. N Engl J Med 343:966CrossRefGoogle Scholar
  4. 4.
    Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS (2002) Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 165:670–676CrossRefGoogle Scholar
  5. 5.
    Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J (2002) Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 166:159–165CrossRefGoogle Scholar
  6. 6.
    De Boeck G, Forsyth RG, Praet M, Hogendoorn PC (2009) Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 217:327–344CrossRefGoogle Scholar
  7. 7.
    Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, Maitre B, Sarni M, Housset B, Weitzenblum E, Matrat M, Le Corvoisier P, Rideau D, Boczkowski J, Dubois-Randé JL, Chouaid C, Adnot S (2009) Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179:566–571CrossRefGoogle Scholar
  8. 8.
    Blackburn EH, Epel ES, Lin J (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350:1193–1198CrossRefGoogle Scholar
  9. 9.
    Yao H, Rahman I (2012) Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol 84:1332–1339CrossRefGoogle Scholar
  10. 10.
    Zeng L, Chen R, Liang F, Tsuchiya H, Murai H, Nakahashi T, Iwai K, Takahashi T, Kanda T, Morimoto S (2009) Silent information regulator, Sirtuin 1, and age-related diseases. Geriatr Gerontol Int 9:7–15CrossRefGoogle Scholar
  11. 11.
    Ota H, Eto M, Ogawa S, Iijima K, Akishita M, Ouchi Y (2010) SIRT1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis. J Atheroscler Thromb17:431–435Google Scholar
  12. 12.
    Weaver TE, Grunstein RR (2008) Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 5:173–178CrossRefGoogle Scholar
  13. 13.
    Chan AS, Lee RW, Cistulli PA (2008) Non-positive airway pressure modalities: mandibular advancement devices/positional therapy. Proc Am Thorac Soc 5:179–184CrossRefGoogle Scholar
  14. 14.
    Lim J, Lasserson TJ, Fleetham J, Wright J (2004) Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 4:CD004435Google Scholar
  15. 15.
    Iber C, Ancoli-Israel S, Chesson AL, Quan SF (2007) The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications, 1st edn. American Academy of Sleep Med, WestchesterGoogle Scholar
  16. 16.
    Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47–e447Google Scholar
  17. 17.
    Barceló A, Piérola J, López-Escribano H, de la Peña M, Soriano JB, Alonso-Fernández A, Ladaria A, Agustí A (2010) Telomere shortening in sleep apnea syndrome. Respir Med 104:1225–1229CrossRefGoogle Scholar
  18. 18.
    LIN L, LI TP (2011) Alteration of telomere length of the peripheral white blood cells in patients with obstructive sleep apnea syndrome. Nan Fang Yi Ke Da Xue Xue Bao 31:457–460Google Scholar
  19. 19.
    Tempaku PF, Mazzotti DR, Hirotsu C, Andersen ML, Xavier G, Maurya PK, Rizzo LB, Brietzke E, Belangero SI, Bittencourt L, Tufik S (2016) The effect of the severity of obstructive sleep apnea syndrome on telomere length. Oncotarget 7:69216–69224CrossRefGoogle Scholar
  20. 20.
    Savolainen K, Eriksson JG, Kajantie E, Lahti M, Räikkönen K (2014) The history of sleep apnea is associated with shorter leukocyte telomere length: the Helsinki birth cohort study. Sleep Med 15:209–212CrossRefGoogle Scholar
  21. 21.
    Riestra P, Gebreab SY, Xu R, Khan RJ, Quarels R, Gibbons G, Davis SK (2017) Obstructive sleep apnea risk and leukocyte telomere length in African Americans from the MH-GRID study. Sleep Breath 21:751–757CrossRefGoogle Scholar
  22. 22.
    Chen WJ, Liaw SF, Lin CC, Chiu CH, Lin MW, Chang FT (2015) Effect of nasal CPAP on SIRT1 and endothelial function in obstructive sleep apnea syndrome. Lung 193:1037–1045CrossRefGoogle Scholar
  23. 23.
    Wang Q, Sun X, Li X, Dong X, Li P, Zhao L (2015) Resveratrol attenuates intermittent hypoxia-induced insulin resistance in rats: involvement of Sirtuin 1 and the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway. Mol Med Rep 11:151–158CrossRefGoogle Scholar
  24. 24.
    Kagawa Y (2012) From clock genes to telomeres in the regulation of the healthspan. Nutr Rev 70:459–471CrossRefGoogle Scholar
  25. 25.
    Pieters N, Janssen BG, Valeri L, Cox B, Cuypers A, Dewitte H, Plusquin M, Smeets K, Nawrot TS (2015) Molecular responses in the telomere-mitochondrial axis of ageing in the elderly: a candidate gene approach. Mech Ageing Dev 145:51–57CrossRefGoogle Scholar
  26. 26.
    De Bonis ML, Ortega S, Blasco MA (2014) SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells. Stem Cell Reports 2:690–706CrossRefGoogle Scholar
  27. 27.
    Kim KS, Kwak JW, Lim SJ, Park YK, Yang HS, Kim HJ (2016) Oxidative stress-induced telomere length shortening of circulating leukocyte in patients with obstructive sleep apnea. Aging Dis 7:604–613CrossRefGoogle Scholar
  28. 28.
    Boyer L, Audureau E, Margarit L, Marcos E, Bizard E, Le Corvoisier P, Macquin-Mavier I, Derumeaux G, Damy T, Drouot X, Covali-Noroc A, Boczkowski J, Bastuji-Garin S, Adnot S (2016) Telomere shortening in middle-aged men with sleep-disordered breathing. Ann Am Thorac Soc 13:1136–1143CrossRefGoogle Scholar
  29. 29.
    Kwon AM, Baik I, Thomas RJ, Shin C (2015) The association between leukocyte telomere lengths and sleep instability based on cardiopulmonary coupling analysis. Sleep Breath 19:963–968CrossRefGoogle Scholar
  30. 30.
    Prather AA, Gurfein B, Moran P, Daubenmier J, Acree M, Bacchetti P, Sinclair E, Lin J, Blackburn E, Hecht FM, Epel ES (2015) Tired telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women. Brain Behav Immun 47:155–162CrossRefGoogle Scholar
  31. 31.
    Choi KM, Thomas RJ, Yoon DW, Lee SK, Baik I, Shin C (2016) Interaction between obstructive sleep apnea and shortened telomere length on brain white matter abnormality. Sleep 39:1639–1645CrossRefGoogle Scholar
  32. 32.
    Marin JM, Carrizo SJ, Vicente E, Agusti AG (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365:1046–1053CrossRefGoogle Scholar
  33. 33.
    Alonso-Fernández A, García-Río F, Arias MA, Hernanz A, de la Peña M, Piérola J, Barceló A, López-Collazo E, Agustí A (2009) Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax 64:581–586CrossRefGoogle Scholar
  34. 34.
    Barnes M, McEvoy RD, Banks S, Tarquinio N, Murray CG, Vowles N, Pierce RJ (2004) Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 170:656–664CrossRefGoogle Scholar
  35. 35.
    Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G (2007) The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 131:740–749CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ching-Chi Lin
    • 1
    Email author
  • Huey-Yuan Wang
    • 2
  • Shwu-Fang Liaw
    • 3
  • Chung-Hsin Chiu
    • 4
  • Mei-Wei Lin
    • 1
  1. 1.Division of Pulmonary Medicine, Department of Internal Medicine, Buddhist Tzu Chi Medical FoundationTaipei Tzu Chi HospitalNew Taipei CityTaiwan
  2. 2.Department of DentistryMackay Memorial HospitalTaipeiTaiwan
  3. 3.Department of Medical ResearchMackay Memorial HospitalTaipeiTaiwan
  4. 4.Chest Division, Department of Internal Medicine, Department of Medical ResearchMackay Memorial HospitalTaipeiTaiwan

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