Different responses to DNA damage determine ageing differences between organs

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.

Purkinje-cell-specific DNA repair-deficient mice reveal that dietary restriction protects neurons by cell-intrinsic preservation of genomic health

“…On the other hand, DR affects numerous intra- and intercellular processes, which include nutrient sensing, metabolic, hormonal and immunoregulatory pathways ( Speakman and Mitchell, 2011 ; Green et al, 2022 ). Thus, a major challenge in understanding the anti-aging mechanisms of DR lies in connecting the pathways modulated by DR with the variety of aging processes that operate distinctively across tissues and cell types ( Speakman and Mitchell, 2011 ; Ma et al, 2020 ; Schaum et al, 2020 ; Vougioukalaki et al, 2022 ).…”

“…Most notably, DR strongly reduced the dramatic, progressive neurodegeneration ( Vermeij et al, 2016a ). Since Ercc1 Δ/− mice develop systemic multimorbidity, with severely compromised functions of vital organs, blood vessels and immune system ( Vermeij et al, 2016a , b ; Vougioukalaki et al, 2022 ), a key question remained whether DR is neuroprotective indirectly via local and/or systemic components (e.g., by reducing inflammation), or by directly lowering cell-intrinsic DNA-damage-driven neurotoxicity. This question is particularly relevant for the central nervous system in view of increasing evidence favoring a central role of systemic factors in nervous system aging and neurodegeneration ( Pluvinage and Wyss-Coray, 2020 ).…”

The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside

“…ERCC1 and XPG (also known as ERCC5) are endonucleases involved in different DNA repair pathways, that each resolve specific types of DNA lesions. Both cut the damaged DNA strand at opposing sites during the essential excision step in the global genome nucleotide excision repair (GG-NER) and transcription-coupled repair (TCR) processes, which removes the wide class of bulky, helix-distorting DNA lesions respectively genome-wide or after they arrest elongating RNA polymerase complexes, interfering with transcription ( Marteijn et al, 2014 ; Vougioukalaki et al, 2022 ). Additionally, ERCC1 is implicated in interstrand crosslink repair and single-strand annealing (that repair DNA crosslinks and double strand DNA breaks respectively), while XPG is also involved in base excision repair (for the removal of subtle, oxidative lesions) ( Klungland et al, 1999 ; Trego et al, 2016 ; Faridounnia et al, 2018 ; Apelt et al, 2021 ).…”

Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases

“…Additionally, certain aging phenotypes are also determined by stochastic processes, including macromolecular damage [ 73 ], which leads to the gradual “wearing and tearing” of cells and tissues [ 74 ]. Part of these age-related changes are driven by increased production of oxygen free radicals [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ] and by the accumulation of cross-linked proteins [ 84 , 85 ] and DNA damage [ 86 , 87 , 88 , 89 , 90 ]. Some of this damage accumulates over time, while some is repaired by different repair mechanisms [ 91 , 92 ].…”