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Original research
Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair
  1. Avital Guedj1,
  2. Yael Volman1,
  3. Anat Geiger-Maor1,
  4. Julia Bolik2,
  5. Neele Schumacher2,
  6. Sven Künzel3,
  7. John F Baines3,4,
  8. Yuval Nevo5,
  9. Sharona Elgavish5,
  10. Eithan Galun1,
  11. Hagai Amsalem6,
  12. Dirk Schmidt-Arras2,
  13. Jacob Rachmilewitz1
  1. 1 Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
  2. 2 Institute of Biochemistry, Kiel University, Kiel, Germany
  3. 3 Institute for Evolutionary Biology, Max Planck, Plön, Germany
  4. 4 Institute for Experimental Medicine, Kiel University, Kiel, Germany
  5. 5 Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel
  6. 6 Department of Obstetrics and Gynecology, Hadassah University Hospital-Mount Scopus, Jerusalem, Israel
  1. Correspondence to Professor Jacob Rachmilewitz, Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel; rjacob444{at}


Objective Failing to properly repair damaged DNA drives the ageing process. Furthermore, age-related inflammation contributes to the manifestation of ageing. Recently, we demonstrated that the efficiency of repair of diethylnitrosamine (DEN)-induced double-strand breaks (DSBs) rapidly declines with age. We therefore hypothesised that with age, the decline in DNA damage repair stems from age-related inflammation.

Design We used DEN-induced DNA damage in mouse livers and compared the efficiency of their resolution in different ages and following various permutations aimed at manipulating the liver age-related inflammation.

Results We found that age-related deregulation of innate immunity was linked to altered gut microbiota. Consequently, antibiotic treatment, MyD88 ablation or germ-free mice had reduced cytokine expression and improved DSBs rejoining in 6-month-old mice. In contrast, feeding young mice with a high-fat diet enhanced inflammation and facilitated the decline in DSBs repair. This latter effect was reversed by antibiotic treatment. Kupffer cell replenishment or their inactivation with gadolinium chloride reduced proinflammatory cytokine expression and reversed the decline in DSBs repair. The addition of proinflammatory cytokines ablated DSBs rejoining mediated by macrophage-derived heparin-binding epidermal growth factor-like growth factor.

Conclusions Taken together, our results reveal a previously unrecognised link between commensal bacteria-induced inflammation that results in age-dependent decline in DNA damage repair. Importantly, the present study support the notion of a cell non-autonomous mechanism for age-related decline in DNA damage repair that is based on the presence of ‘inflamm-ageing’ cytokines in the tissue microenvironment, rather than an intrinsic cellular deficiency in the DNA repair machinery.

  • liver
  • DNA damage
  • kupffer cell
  • inflammation
  • ageing

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  • Contributors JR and AG designed the research and analysed the data. JR wrote the manuscript. AG prepared the manuscript. YV and AG-M performed experiments. YN and SE analysed the RNAseq data. HA and EG contributed to experimental design and data analysis. SK and JFB provided germ-free mice, performed the experiments and RNA sequencing. DS-A supervised experiments, analysed RNAseq data and contributed to writing the manuscript.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Experimental protocol was approved by the Hebrew University Institutional Animal Care and Ethical Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.