Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study


Mohsen Mazidi | Niloofar Shekoohi | Niki Katsiki | Michal Rakowski | Dimitri P. Mikhailidis | Maciej Banach

First published: 21 April 2021 |


The relationship between inflammatory and anti-inflammatory markers and telomere length (TL), a biological index of aging, is still poorly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reactive protein (CRP), leptin, and serum uric acid (SUA) with TL.

Material and methods:
MR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.

With regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estimations, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible intercepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).

Our results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.

Full content publication available for download

  1. Hayashi MT. (2018). Telomere biology in aging and cancer: early history and perspectives Genes Genet Syst. 92: 107-18.
  2. Gill ZNieuwoudt MNdifon W. (2018). The Hayflick limit and age-related adaptive immune deficiency Gerontology. 64: 135-9.
  3. Kline KABowdish DM. (2016). Infection in an aging population Curr Opin Microbiol. 29: 63-7.
  4. Vadasz ZHaj TKessel AToubi E. (2013). Age-related autoimmunity BMC Med. 11: 94
  5. Trocha MMerwid-Lad APiesniewska Met al. (2018). Age-related differences in function and structure of rat livers subjected to ischemia/reperfusion Arch Med Sci. 14: 388-95.
  6. Xu WLarbi A. (2017). Markers of T cell senescence in humans Int J Mol Sci. 18.
  7. Yaqoob P. (2017). Ageing alters the impact of nutrition on immune function Proc Nutr Soc. 76: 347-51.
  8. Montgomery RR. (2017). Age-related alterations in immune responses to West Nile virus infection Clin Exp Immunol. 187: 26-34.
  9. Gavazzi GKrause KH. (2002). Ageing and infection Lancet Infect Dis. 2: 659-66
  10. Ginaldi LLoreto MFCorsi MPModesti MDe Martinis. (2001). Immunosenescence and infectious diseases Microbes Infect. 3: 851-7.Ginaldi
  11. LDe MartinisD’Ostilio Aet al. (1999). The immune system in the elderly: II. Specific cellular immunity Immunol Res. 20: 109-15.
  12. De GreefVan TolKallenberg CGet al. (1992). Influence of ageing on antibody formation in vivo after immunisation with the primary T-cell dependent antigen Helix pomatia haemocyanin Mech Ageing Dev. 66: 15-28.
  13. Kendall MD. (1981). The thymus and haemopoiesis Prog Clin Biol Res. 59B: 221-30.
  14. Steinmann GG. (1986). Changes in the human thymus during aging Curr Top Pathol. 75: 43-88.
  15. Fagnoni FFVescovini RMazzola Met al. (1996). Expansion of cytotoxic CD8+ CD28– T cells in healthy ageing people, including centenarians Immunology. 88: 501-7.
  16. Herndler-Brandstetter DSchwaiger SVeel Eet al. (2005). CD25- expressing CD8+ T cells are potent memory cells in old age J Immunol. 175: 1566-74.
  17. Peres ABauer Mda CruzNardi NBChies JA. (2003). Immunophenotyping and T-cell proliferative capacity in a healthy aged population Biogerontology. 4: 289-96.
  18. French ALMcCullough MERice KTSchultz MEGordin FM. (1998). The use of tetanus toxoid to elucidate the delayed-type hypersensitivity response in an older, immunized population Gerontology. 44: 56-60.
  19. Mastroeni IVescia NPompa MGCattaruzza MSMarini GPFara GM. (1994). Immune response of the elderly to rabies vaccines Vaccine. 12: 518-20.
  20. Fagiolo UAmadori ACozzi Eet al. (1993). Humoral and cellular immune response to influenza virus vaccination in aged humans Aging. 5: 451-8.
  21. Saurwein-Teissl MLung TLMarx Fet al. (2002). Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines J Immunol. 168: 5893-9.
  22. Negoro SHara HMiyata Set al. (1986). Mechanisms of age-related decline in antigen-specific T cell proliferative response: IL-2 receptor expression and recombinant IL-2 induced proliferative response of purified Tac-positive T cells Mech Ageing Dev. 36: 223-41.
  23. Hodes RJHathcock KSWeng NP. (2002). Telomeres in T and B cells Nat Rev Immunol. 2: 699-706.
  24. Burns JBLobo STBartholomew BD. (2000). In vivo reduction of telomere length in human antigen-reactive memory T cells Eur J Immunol. 30: 1894-901.
  25. Kohler SWagner UPierer Met al. (2005). Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults Eur J Immunol. 35: 1987-94.
  26. Fulop TUtsuyama MHirokawa K. (1991). Determination of interleukin 2 receptor number of Con A stimulated human lymphocytes with aging J Clin Lab Immunol. 34: 31-6.
  27. Weng NP. (2008). Telomere and adaptive immunity Mech Ageing Dev. 129: 60-6.
  28. Kaszubowska L. (2008). Telomere shortening and ageing of the immune system J Physiol Pharmacol. 59: 169-86.
  29. Hemann MTStrong MAHao LYGreider CW. (2001). The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability Cell. 107: 67-77.
  30. Hemann MTRudolph KLStrong MADePinho RAChin LGreider CW. (2001). Telomere dysfunction triggers developmentally regulated germ cell apoptosis Mol Biol Cell. 12: 2023-30.
  31. Igarashi HSakaguchi N. (1996). Telomerase activity is induced by the stimulation to antigen receptor in human peripheral lymphocytes Biochem Biophys Res Commun. 219: 649-55.
  32. Wallace DLBerard MSoares MVet al. (2006). Prolonged exposure of naive CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length Immunology. 119: 243-53.
  33. Yang YAn JWeng NP. (2008). Telomerase is involved in IL-7-mediated differential survival of naive and memory CD4+ T cells J Immunol. 180: 3775-81.
  34. Mazidi MPenson PBanach M. (2017). Association between telomere length and complete blood count in US adults Arch Med Sci. 13: 601-5.
  35. Athie-Morales VSmits HHCantrell DAHilkens CM. (2004). Sustained IL-12 signaling is required for Th1 development J Immunol. 172: 61-9.
  36. Cantrell DASmith KA. (1984). The interleukin-2 T-cell system: a new cell growth model Science. 224: 1312-6.
  37. Smith KA. (1992). Interleukin-2 Curr Opin Immunol. 4: 271-6.
  38. Cawthon RM. (2002). Telomere measurement by quantitative PCR Nucleic Acids Res. 30: e47.
  39. Halaschek-Wiener JVulto IFornika Det al. (2008). Reduced telomere length variation in healthy oldest old Mech Ageing Dev. 129: 638-41.
  40. Wallace DLZhang YGhattas Het al. (2004). Direct measurement of T cell subset kinetics in vivo in elderly men and women J Immunol. 173: 1787-94.
  41. Farrag WEid MEl-Shazly SAbdallah M. (2011). Angiotensin II type 1 receptor gene polymorphism and telomere shortening in essential hypertension Mol Cell Biochem. 351: 13-8.
  42. Yang ZHuang XJiang Het al. (2009). Short telomeres and prognosis of hypertension in a Chinese population Hypertension. 53: 639-45.
  43. Akbar ANVukmanovic-Stejic M. (2007). Telomerase in T lymphocytes: use it and lose it? J Immunol. 178: 6689-94.
  44. Reed JRVukmanovic-Stejic MFletcher JMet al. (2004). Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo J Exp Med. 199: 1433-43.
  45. Yang LSuwa TWright WEShay JWHornsby PJ. (2001). Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells Mech Ageing Dev. 122: 1685-94.
  46. Lin YDamjanovic AMetter EJet al. (2015). Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions Clin Sci. 128: 367-77