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.
|Publication status||Published - Apr 2022|
M.V., J.H.J.H. and J.P. acknowledge funding from Marie Curie ITN program MARIAGE. Financial support was obtained from NIH/NIA (PO1 AG017242), European Research Council Advanced Grants DamAge, Dam2Age, and PoC Grant Dementia to J.H.J.H., the KWO award and Oncode, supported by the Dutch Cancer Society (5030), Deutsche Forschungsgemeinschaft (DFG) Projekt 73111208 - SFB 829. Additional support was obtained from ‘Memorabel’ (Medical Sciences) and EJP-RD project TC-NER. The authors are indebted to Dr. Masaki Akita for 6,4 photoproduct immunostaining, Tsun Wai Kan for cell sorting and Dr. Georgios Gkouridis for comments on the manuscript.
© 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.