FIGURE 7.

Tentative model for organ‐specific anti‐ageing strategies. Remaining cellular lifespan largely determines which DNA damage response strategy is preferred by organs/tissues to counteract ageing. For intestine, cell death is preferred, as cells have to function only for 3–5 days and cell loss can be compensated by increased (stem) cell proliferation. Obviously, this is very energy‐demanding (daily a human body produces 200 gram intestinal epithelium) and unaffordable for many organs. Other tissues with continuous but slower cell renewal such as the hematopoietic system (average cell turn‐over ~2 months) rely mostly on replication‐related repair (such as NHEJ/HR and XLR) and apoptosis (Hoeijmakers, 2001). Skin, as an organ with high UV exposure and also intermediate cell renewal combines GG‐NER and TCR with apoptosis and premature differentiation of damaged stem cells (Kim et al., 2020). Finally, tissues with slow (e.g., liver, on average ~1 year) or no cell turn‐over (e.g., the central nervous system, life time) depend on constitutive (cell cycle independent) DNA repair systems, most notably TCR to permit long‐term unperturbed use of the transcribed compartment of the genome, needed for sustained proper cellular functioning. Global genome repair systems (base and nucleotide excision repair) are probably important for all organs and tissues for preventing mutagenesis and permit survival. TLS allows replication bypass of lesions to rescue stalled replication and cellular proliferative capacity, however, at the expense of elevated mutagenesis and cancer risk. Cellular (replicative) senescence opposes cell death in most organs. This model explains the segmental nature of repair‐deficient progeroid syndromes, in which inherited deficiencies in different repair systems are associated with a different subset of organs and tissues displaying accelerated ageing.

¹Not including mismatch repair, which is a replication error correction system, important for preventing mutations and cancer, particularly in highly proliferative tissues such as intestine. GG‐NER, global genome nucleotide excision repair; NHEJ/HR, Non‐Homologous End‐Joining/Homologous recombination repair two pathways for double strand break repair; TCR, transcription‐coupled repair; TLS, translesion synthesis; XLR, cross‐link repair