Different responses to DNA damage determine ageing differences between organs

Maria Vougioukalaki, Joris Demmers, Wilbert P Vermeij, Marjolein Baar, Serena Bruens, Aristea Magaraki, Ewart Kuijk, Myrthe Jager, Sarra Merzouk, Renata M C Brandt, Janneke Kouwenberg, Ruben van Boxtel, Edwin Cuppen, Joris Pothof, Jan H J Hoeijmakers

Research output: Contribution to journalArticlepeer-review

Abstract

Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ/− mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ/− intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over-proliferation. ISCs retain their organoid-forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1-KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1Δ/− liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA-damaging agents, and lower lesion removal. Our findings reveal organ-specific anti-ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self-renewal mainly invokes replication-linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA-repair-deficient progerias.
Original languageEnglish
Pages (from-to)e13562
JournalAging cell
Volume21
Issue number4
DOIs
Publication statusPublished - 1 Apr 2022
Externally publishedYes

Keywords

  • DNA damage response
  • ERCC1
  • adult stem cells
  • genome maintenance
  • liver
  • nucleotide excision repair
  • organoids
  • small intestine

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