New research shows that resveratrol, a chemical found in red wine, contributes to genomic stability by reducing the occurrence of DNA double-strand breaks and prolongs lifespan in genetically modified mice that are prone to carcinogenic mutations [1].
DSBs and genomic instability
Genomic instability, one of the hallmarks of aging, is a condition characterized by frequent mutations within the genome, and it has long been associated with cancer [2]. The authors of this study state that one of its major causes is the erroneous repair of DNA double-strand breaks (DSBs). High numbers of DSBs have been found in pre-cancerous cells, and DNA lesions caused by unrepairable DSBs accumulate with time, both in organisms and in cultured cells. One of the possible culprits is the degradation of DNA repair mechanisms in aged cells [3].
DSBs are among the most detrimental factors affecting genomic stability. While various instances of DNA damage can happen as often as 100,000 times a day in a single cell [4], DSBs are much rarer and more dangerous, and they can occur due to replication stress, irradiation, or other factors. Replication stress is a complex and not fully defined phenomenon that includes the slowing or stalling of replication fork progression (the process of unzipping the double strand for duplication) and/or DNA synthesis [5].
A DSB occurs when both of the strands of DNA break in close proximity, typically within 10-20 base pairs. If not repaired quickly, DSBs can cause cellular death, chromosomal aberrations, mutations, and cancer. Cells utilize some intricate machinery to repair DSBs, much of which is controlled by certain histones (proteins around which DNA is wrapped). The initial message that a DSB has occurred is generated by the phosphorylation of a histone of this type, called H2AX, at the breakage site. This attracts various elements of the DNA damage response (DDR), which arrive at the scene to commence the repair. γH2AX (the phosphorylated version of H2AX) helps them by holding the broken ends together and halting cellular division to make time for the repair. It also seems to regulate the end result: if the repair was successful, cellular division can proceed. Otherwise, the cell may die through apoptosis or cease to divide [6].
Several years ago, γH2AX histones were found to be an extremely accurate cellular marker of DSBs, since they appear only when a break occurs and disappear shortly after the event’s resolution. One appearance of a γH2AX histone corresponds to a single DSB.
The two experiments
Resveratrol is a polyphenol that is found in many edible plants. Resveratrol and its cousin pterostilbene, which was not part of this study, are probably the most well-known polyphenols. The first is commonly associated with red wine and the second with berries, although both are also found in other edible products. Numerous animal studies have shown that polyphenols, when consumed regularly, can contribute to cancer suppression and lifespan extension. Resveratrol is known to activate sirtuins, proteins implicated, among other things, in DNA repair [7]. The current study measures γH2AX to determine whether the beneficial effects of resveratrol and some other polyphenols can be linked to the prevalence of DSBs.
In the first experiment, conducted in vitro, the researchers grew mouse embryonic fibroblast cells (MEFs) under a protocol that induces abnormal cellular stress and eventually leads to senescence and immortalization with high levels of genomic instability. As expected, MEFs grown under the standard protocol became immortalized with tetraploidy, a pathology in which a cell ends up with four sets of chromosomes instead of two. MEFs that were regularly treated with resveratrol had maintained genomic stability and were protected against immortalization. The authors monitored γH2AX and found that γH2AX foci were significantly reduced in number after the cells were treated with resveratrol. The experiment also showed that resveratrol causes a transient rise in the levels of H2AX – which is probably the mechanism behind the increased efficacy of DSB repair.
The authors repeated the experiment with chlorogenic acid, a polyphenol found in coffee, and melinjo resveratrol, a mixture of several resveratrol-associated polyphenols found in melinjo seeds, and saw largely similar results. It is worth noting, though, that only one of the three major polyphenols found in melinjo seeds (gnetin C) showed a positive effect.
Melinjo resveratrol was then used in the second, in vivo, experiment, in mice with a knocked-out Msh2 gene, which causes them to exhibit high rates of mutation and cancer. Such mice fed a diet containing melinjo resveratrol exhibited a significantly longer lifespan than the control group. This does not necessarily prove that resveratrol can extend lifespan in healthy animals, although such results have been achieved in other studies [8], but this study shows that it significantly contributes to the survivability of mice prone to carcinogenic mutations.
Conclusion
The authors suggest that maintaining genomic stability would likely prevent the formation of mutations and suppress cancer development. Some cancer types are associated with mutations randomly induced during DNA replication, which are probably unavoidable. However, others have been specifically linked to genomic instability, a condition that can potentially be treated by reinforcing cellular repair mechanisms. The degradation of such mechanisms with age adds weight to the well-established link between cancer and aging. Resveratrol and other similar compounds have long been known for their cancer-mitigating and life-prolonging qualities. The current research provides an intriguing possible explanation for these qualities that can be relevant for future cancer and longevity research.
Literature
[1] Matsuno, Y., Atsumi, Y., Alauddin, M., Rana, M. M., Fujimori, H., Hyodo, M., … & Nakatsu, Y. (2020). Resveratrol and its Related polyphenols contribute to the Maintenance of Genome Stability. Scientific Reports, 10(1), 1-10.
[2] Schmitt, M. W., Prindle, M. J., & Loeb, L. A. (2012). Implications of genetic heterogeneity in cancer. Annals of the New York Academy of Sciences, 1267, 110.
[3] Sedelnikova, O. A., Horikawa, I., Zimonjic, D. B., Popescu, N. C., Bonner, W. M., & Barrett, J. C. (2004). Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature cell biology, 6(2), 168-170.
[4] Hoeijmakers, J. H. (2009). DNA damage, aging, and cancer. New England Journal of Medicine, 361(15), 1475-1485.
[5] Zeman, M. K., & Cimprich, K. A. (2014). Causes and consequences of replication stress. Nature cell biology, 16(1), 2-9.
[6] Mah, L. J., El-Osta, A., & Karagiannis, T. C. (2010). γH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia, 24(4), 679-686.
[7] Mei, Z., Zhang, X., Yi, J., Huang, J., He, J., & Tao, Y. (2016). Sirtuins in metabolism, DNA repair and cancer. Journal of Experimental & Clinical Cancer Research, 35(1), 182.
[8] Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852(6), 1209-1218.
