DNA Damages

There are plenty of sources for the occuring of DNA-damages within our bodies, generated from normal cellular metabolism to environmental stressors (like free radicals or UV light). Mammalian cells evolved a delicate repair-system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent the damage from both endogenous end exogenous insults. Emerging evidence suggests that aberrant DDR and deficient DNA repair are strongly associated with cancer and aging (Mei-Ren Pan et al., 2016).  Our understanding of the core program of DDR has made tremendous progress in the past two decades.

Currently, four repair mechanisms for damaged DNA have been elucidated in mammalian cells. Base excision repair (BER) mainly corrects single lesions or small alternations of bases. Nucleotide excision repair (NER) is a more complex process involving the removal of bulky DNA lesions. Homologous recombination (HR) and non-homologous end joining (NHEJ) mainly work on double-strand break (DSB) repair. Different types of DNA damage could be fixed by specific repair mechanisms.

Based on the evidence of cellular senescence, intensive investigations have been carried out to address the role of DDR proteins in aging. DNA repair–deficient nematodes have a significantly shorter life span while several long-living mutants show increased repair activity, suggesting DNA repair capacity influences the aging process and affects longevity in nematodes (Hyun et al., 2008).

But there is also evidence found int human genetic defects including CS and XP also suggest that deficient DNA repair leads to tissue degeneration and premature aging. CS is an autosomal recessive disease mainly caused by mutations in Cockayne syndrome group A (CSA) (also known as excision repair cross-complementation group 8, ERCC8) and Cockayne syndrome group B (CSB) (also known as ERCC6) genes. Both genes participate in the excision repair pathways (Lindahl et al., 1997). CS patients show impairment of the nervous system, hypersensitivity to sunlight, retinal disorder and premature aging (Bertola et al. 2006, Bender et al., 2003). Similarly, XP patients have photosensitivity of the skin and eye and exhibit premature cutaneous aging with increased incidence of basal cell carcinoma and melanoma (Robbins et al., 1974, Robbins, 1988). The characteristics of the CS and XP patients also suggest that DNA repair is closely associated with aging.

Many previous studies addressing the senescence mechanism were done in single cells, especially in fibroblasts. An obvious question is how cellular senescence caused by deficient DNA repair finally affects the aging of a living organism. Currently there are three potential mechanisms hypothesised to explain the systemic effect (Mei-Ren Pan et al., 2016) . First, senescence depletes the supplemental pool of stem cells or progenitor cells that leads to the continuous decline of tissue homeostasis and accelerates organ aging.

Secondly, senescence causes tissue degeneration. As evidenced in human diseases,
defects in DNA repair induce senescence and degeneration of nervous and endocrine/exocrine tissues. Dysfunction of the nervous system would decrease the activity of innervated tissues and dysfunction of the endocrine/exocrine system would disturb hormone homeostasis and nutrient balance which ultimately causes organ aging. Thirdly, senescence induces chronic inflammation. One well-known production of pro-inflammatory and matrix-degrading molecules, known as the senescence-associated secretory phenotype (SASP) (Childs et al., 2015, Coppé et al., 2008). Higher serum levels of pro-inflammatory factors such as interleukin-6 and tumor necrosis factor are found in aged mice (Morin et al., 1997, Starr et al., 2009). A similar observation is also confirmed in aged individuals (Maggio et al., 2008). Chronic inflammation triggered by these pro-inflammatory factors changes the immune response and vascular system and finally disrupts the physiological function of many tissues to promote the aging process (Freund et al., 2010).  

Our understanding of DDR and DNA repair has tremendously advanced in the past two decades. In addition, the role of DDR and repair in cancer and normal or pathological aging has become much clearer. However, the translation of the knowledge into clinical application is still at a very early stage.

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