Advertisement

l-Carnitine inhibits the senescence-associated secretory phenotype of aging adipose tissue by JNK/p53 pathway

  • Lian-wei Yang
  • Ming Song
  • Yu-lin Li
  • Ya-peng Liu
  • Chun Liu
  • Lu Han
  • Zhi-hao Wang
  • Wei Zhang
  • Yan-qiu Xing
  • Ming Zhong
Research Article

Abstract

Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of l-carnitine, an inhibitor of the JNK/p53 pathway in adipose tissue SASP and dysfunction. Young and aging rat were given l-carnitine by gavage. Next, we detected the senescence, cytokines expression, chronic inflammation and insulin resistance of adipose tissue. Additionally, JNK/p53 pathway was estimated. Our results show a significant increase expression of SASP components in the adipose tissue of aging rats compared to young rats. Further, we found that infiltration of immune cells and the expression of pro-inflammatory cytokines were enhanced in aging adipose tissue while insulin signaling activity was reduced in aging adipose tissue. Interestingly, l-carnitine markedly reduced the expression of SASP factors. l-Carnitine could significantly reduce chronic inflammation, improving insulin resistance. Further, l-carnitine inhibited SASP by inhibiting JNK/p53 pathway. l-Carnitine inhibited SASP by JNK/p53 pathway and attenuated adipose tissue dysfunction of aging.

Keywords

Aging SASP Adipose tissue l-Carnitine 

Notes

Acknowledgements

This work was supported by the research Grants from the National Natural Science Foundation of China (81702194, 81600633, 81670411, 81570400, 81470560, 81471036), Key research and development program of Shandong Province (2018GSF118002, 2018GSF118017, 2017GSF18156), the Natural Science Foundation of Shandong Province (ZR2014HQ037, ZR2017BH023).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

References

  1. Feng X, Liu H, Zhang Z, Gu Y, Qiu H, He Z (2017) Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res 36:123.  https://doi.org/10.1186/s13046-017-0594-1 CrossRefPubMedGoogle Scholar
  2. Freund A, Patil CK, Campisi J (2011) p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 30:1536–1548.  https://doi.org/10.1038/emboj.2011.69 CrossRefPubMedGoogle Scholar
  3. Jin HJ et al (2016) Senescence-associated MCP-1 secretion is dependent on a decline in BMI1 in human mesenchymal stromal cells. Antioxid Redox Signal 24:471–485.  https://doi.org/10.1089/ars.2015.6359 CrossRefPubMedGoogle Scholar
  4. Li Q, Qi F, Meng X, Zhu C, Gao Y (2018) Mst1 regulates colorectal cancer stress response via inhibiting Bnip3-related mitophagy by activation of JNK/p53 pathway. Cell Biol Toxicol 34:263–277.  https://doi.org/10.1007/s10565-017-9417-6 CrossRefPubMedGoogle Scholar
  5. Liu M et al (2017) Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties. Cell Transplant 26:1505–1519.  https://doi.org/10.1177/0963689717721221 CrossRefPubMedGoogle Scholar
  6. Lumeng CN et al (2011) Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol 187:6208–6216.  https://doi.org/10.4049/jimmunol.1102188 CrossRefPubMedGoogle Scholar
  7. Martyniak K, Masternak MM (2017) Changes in adipose tissue cellular composition during obesity and aging as a cause of metabolic dysregulation. Exp Gerontol 94:59–63.  https://doi.org/10.1016/j.exger.2016.12.007 CrossRefPubMedGoogle Scholar
  8. Mobarak H, Fathi E, Farahzadi R, Zarghami N, Javanmardi S (2017) L-carnitine significantly decreased aging of rat adipose tissue-derived mesenchymal stem cells. Vet Res Commun 41:41–47.  https://doi.org/10.1007/s11259-016-9670-9 CrossRefPubMedGoogle Scholar
  9. Nakamura M, Ohsawa S, Igaki T (2014) Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila. Nat Commun 5:5264.  https://doi.org/10.1038/ncomms6264 CrossRefPubMedGoogle Scholar
  10. Olivieri F, Albertini MC, Orciani M, Ceka A, Cricca M, Procopio AD, Bonafe M (2015) DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget 6:35509–35521.  https://doi.org/10.18632/oncotarget.5899 CrossRefPubMedGoogle Scholar
  11. Palmer AK, Kirkland JL (2016) Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 86:97–105.  https://doi.org/10.1016/j.exger.2016.02.013 CrossRefPubMedGoogle Scholar
  12. Rodier F et al (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979.  https://doi.org/10.1038/ncb1909 CrossRefPubMedGoogle Scholar
  13. Stout MB, Justice JN, Nicklas BJ, Kirkland JL (2017) Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda) 32:9–19.  https://doi.org/10.1152/physiol.00012.2016 CrossRefGoogle Scholar
  14. Tousson E, Hafez E, Zaki S, Gad A (2014) P53, Bcl-2 and CD68 expression in response to amethopterin-induced lung injury and ameliorating role of L-carnitine. Biomed Pharmacother 68:631–639.  https://doi.org/10.1016/j.biopha.2014.05.007 CrossRefPubMedGoogle Scholar
  15. Tousson E, Hafez E, Zaki S, Gad A (2016) The cardioprotective effects of L-carnitine on rat cardiac injury, apoptosis, and oxidative stress caused by amethopterin. Environ Sci Pollut Res Int 23:20600–20608.  https://doi.org/10.1007/s11356-016-7220-1 CrossRefPubMedGoogle Scholar
  16. Volonte D, Zou H, Bartholomew JN, Liu Z, Morel PA, Galbiati F (2015) Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6). J Biol Chem 290:4202–4214.  https://doi.org/10.1074/jbc.m114.598268 CrossRefPubMedGoogle Scholar
  17. Xu M et al (2015a) Targeting senescent cells enhances adipogenesis and metabolic function in old age Elife 4:e12997.  https://doi.org/10.7554/eLife.12997 CrossRefPubMedGoogle Scholar
  18. Xu M et al (2015b) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci USA 112:E6301–6310.  https://doi.org/10.1073/pnas.1515386112 CrossRefPubMedGoogle Scholar
  19. Ye J, Han Y, Chen X, Xie J, Liu X, Qiao S, Wang C (2014) L-carnitine attenuates H2O2-induced neuron apoptosis via inhibition of endoplasmic reticulum stress. Neurochem Int 78:86–95.  https://doi.org/10.1016/j.neuint.2014.08.009 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Lian-wei Yang
    • 1
    • 2
  • Ming Song
    • 1
  • Yu-lin Li
    • 1
  • Ya-peng Liu
    • 1
  • Chun Liu
    • 1
    • 4
  • Lu Han
    • 1
    • 3
  • Zhi-hao Wang
    • 1
    • 4
  • Wei Zhang
    • 1
  • Yan-qiu Xing
    • 1
    • 4
  • Ming Zhong
    • 1
  1. 1.The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of CardiologyQilu Hospital of Shandong UniversityJinanChina
  2. 2.Department of CardiologyWeihai Municipal HospitalWeihaiChina
  3. 3.Department of General PracticeQilu Hospital of Shandong UniversityJinanChina
  4. 4.Department of Geriatric Medicine, Key Laboratory of Cardiovascular Proteomics of Shandong ProvinceQilu Hospital of Shandong UniversityJinanChina

Personalised recommendations