Today, we want to bring your attention to a new review that takes an in-depth look at genomic instability, senescent cell accumulation, and its role in aging.
DNA damage as a driver of aging
Genomic instability, otherwise known as DNA damage, is thought by many researchers to be a primary reason why we age. Damage to, and imperfect repair of, the genomes of stem and progenitor cells causes mutations, which are then passed to the somatic cells they create .
Another potential way that DNA damage may contribute to the aging process is through cellular senescence, which causes cells to cease dividing and start to secrete a cocktail of inflammatory signals known as the senescence-associated secretory phenotype (SASP). The immune system normally removes these senescent cells quickly, but as we age and the immune system begins to break down, more and more of these cells accumulate and cause ever-increasing levels of chronic inflammation.
There is also a strong correlation between a species’ ability to repair and maintain its genome and its lifespan, so the case for DNA damage in aging is fairly compelling.
This review takes a high-level look at how DNA damage contributes to aging and is well worth reading if you are interested in learning more about genomic instability .
During an organism’s lifetime, cells are constantly exposed to exogenous and endogenous stressful agents. Cells can cope with these stressors by various response mechanisms, or in case of irreversible damage, programmed cell death (apoptosis), or permanent cell-cycle arrest (cellular senescence). Cellular senescence is characterized by a halt in cellular replication, accompanied by a specific molecular phenotype. This phenotype can be the result of a few factors, such as accumulation of DNA damage, telomere attrition, and various epigenetic alterations.
Cellular senescence is one of the cellular pathways contributing to organismal aging. Senescent cells can accumulate in tissues and organs and can ultimately result in tissue lesions that will cause organ dysfunction, such as through the senescence-associated secretory phenotype (SASP). Age-related accumulation of DNA damage has been studied thoroughly, showing correlation between age and damage levels or mutation frequency. In the presence of DNA lesions or abnormalities, the DNA damage response (DDR) is activated and can eventually lead to cell cycle arrest. In older organisms, accumulation of DNA damage and loss of regenerative potential consequently increase the number of senescent cells, leading to aging cells, tissues, organs, and inevitable death.
The accumulation of genomic abnormalities is influenced by the quality of the repair pathways, which may also decline with age. Researchers studied age-related DNA damage in peripheral blood cells using single nucleotide polymorphism (SNP) microarray data from over 50,000 individuals. The frequency of detectable genomic abnormalities was low (less than 0.5%) at birth and rose to 2-3% in 50-year-old donors. Peripheral blood cells were also studied using whole-exome sequencing data from DNA of 17,182 individuals lacking hematologic phenotypes. Somatic mutations were rare in young donors (~40 years old) but became more frequent with age. Furthermore, while studying subjects at 70-79 years, compared with 90-108 years, mutation frequency rose from 9.5 to 18.4%, respectively.
In conclusion, the connection between DNA damage and aging is emphasized by the secretion of senescence-associated proteins during cellular senescence, a phenotype which is activated by DNA damage and is common for both human and mice. Though much progress has been achieved, full understanding of these mechanisms has still a long way to go.
The case for the contribution of DNA damage to aging is growing as more research is conducted. Potential therapies that can address DNA damage may, therefore, be of great value in treating age-related diseases.
 López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
 Lidzbarsky, G., Gutman, D., Shekhidem, H. A., Sharvit, L., & Atzmon, G. (2018). Genomic Instabilities, Cellular Senescence, and Aging: In Vitro, In Vivo and Aging-Like Human Syndromes. Frontiers in medicine, 5.