A Review of DNA Damage, DNA Repair, and Aging

Mutational damage to nuclear DNA increases with age, and this is one of the reasons as to why cancer is predominantly an age-related disease. The more damage there is, the more likely that some of that damage causes a cell to run wild as the seed of a cancer. Beyond this, there is some debate over whether or not nuclear DNA damage produces a significant contribution to aging by dysregulation of cellular behavior, though the mainstream consensus at this point - in advance of any definite study proving the point - is that it probably does. To a large degree this is based on the observation that any breakdown of the extremely efficient DNA repair mechanisms present in our cells produces a range of conditions, many of which appear superficially similar to aging. The point is subtle, however: if aging is damage, there are many ways to generate cell and tissue damage in a living organism that have no particular relevance to aging, even though they also result in disability and death.

Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent damage. DNA carries the inheritable genetic information for all living organisms. However, DNA receives endogenous and exogenous insults every minute and the lesions (approximately 10^4-10^5 per cell per day) are extremely deleterious to cells. These lesions, if not correctly repaired, will interrupt genome replication and transcription and cause wide-scale chromosomal aberrations that trigger malignant transformation or cell death. Therefore, effective sensing and repair systems are developed during evolution to eliminate the DNA lesions and to maintain genome integrity. Dysregulation of DDR and repair is closely associated with human diseases such as cancers, cardiovascular disease, neurodegenerative disorders and aging.

Aging is defined as a progressive decline of body function and a decrease of physiological response to stress that ultimately results in death. Because the insufficiency of repair will cause the accumulation of DNA damage which leads to cell death or functional defect, it is reasonable to hypothesize that DDR and repair is closely associated with aging. Indeed, mice defective in DNA repair exhibit features of premature aging. Human genetic diseases with DNA repair defects such as Huchinson-Gilford Progeria all show premature aging. However, not all DNA damage and repair cause aging. Defects in mismatch repair (MMR) may result in cancer formation but not directly correlate with aging. Interestingly, an accumulation of DNA damage or defect in DNA repair also promotes cellular senescence and apoptosis. This raises the question whether senescence induced by physiological or pathological alterations may be involved in 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. We propose three potential mechanisms to explain the systemic effect. 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 characteristic of senescent cells is the production of pro-inflammatory and matrix-degrading molecules, known as the senescence-associated secretory phenotype (SASP). Higher serum levels of pro-inflammatory factors such as interleukin-6 and tumor necrosis factor are found in aged mice. A similar observation is also confirmed in aged individuals. 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.

Link: http://www.mdpi.com/1422-0067/17/5/685/htm


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