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, 35 (22), 7417-28

DNA Damage, Cellular Senescence and Organismal Ageing: Causal or Correlative?


DNA Damage, Cellular Senescence and Organismal Ageing: Causal or Correlative?

Jian-Hua Chen et al. Nucleic Acids Res.


Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.


Figure 1.
Figure 1.
DNA damage response is a central mediator in triggering cellular senescence. Telomere shortening resulting from end-replication problem or stochastic loss, and various other stressors such as acute oxidative stress treatment, ionizing radiation, overexpression of oncogenes, forced telomere uncapping and exposure to T-oligos all trigger a DNA damage response during induction of cellular senescence. The signalling pathways activated by DNA damage response converge on the p53 and Rb proteins with the p53–p21–Rb pathway mediating senescence due primarily to telomere shortening while p16–Rb pathway mediates premature senescence. Images shown are DNA damage foci detected by immunofluorescence microscopy using anti-γH2AX and 53BP1 antibodies (top), and a senescent human fibroblast cell detected with SA-β-Gal (bottom).
Figure 2.
Figure 2.
Two possible pathways through which cellular senescence may contribute to the ageing process. (A) Cellular senescence may reduce self-renewing cells, thus causing impaired regeneration of tissues. (B) Cellular senescence may cause disrupted tissue structure, local inflammation and permissive microenvironment for neoplastic growth through secretion of degradative enzymes, inflammatory cytokines and epithelial growth factors. Both pathways can cause compromised tissue homeostasis and function which ultimately lead to ageing.
Figure 3.
Figure 3.
Major components that contribute to age-related accumulation of DNA damage and the subsequent consequences that lead to ageing. Age-related increase in ROS production and decline in DNA repair capacity have been identified as two major factors that cause age-associated accumulation of DNA damage. It is less clear as to how the antioxidant defence systems influence increased accumulation of DNA damage during ageing. At the cellular levels DNA damage results in cellular senescence or apoptosis, which in turn lead to compromised tissue homeostasis through stem cell depletion and/or disrupted tissue structure as detailed in Figure 2. Ultimately organ function declines and phenotypical features of ageing manifest at organismal level.

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