International Business Department           Liu Bojia           April 16, 2023

  A significant portion of the East Asian population will experience redness of the skin after drinking alcohol or alcoholic beverages. This phenomenon is mainly due to a defect in a gene called ALDH2 in the body, which leads to inadequate metabolism of alcohol (ethanol) by the liver, and the intermediate product, acetaldehyde, cannot be further converted into non-toxic acetic acid. Instead, the toxic substance acetaldehyde accumulates in the body and causes redness of the skin.

  However, redness is only a minor problem caused by aldehydes; of greater concern is the toxicity of aldehydes to cells.The protein encoded by ALDH2 is also an indispensable enzyme for the breakdown of formaldehyde. When aldehydes are not removed efficiently, they become highly reactive with DNA and proteins within the cell, causing multiple forms of DNA damage that can lead to cell death.

  A new study recently published in Nature Cell Biology, a sub-journal of Nature, found a strong link between DNA damage caused by endogenous aldehydes and ag ing. " We found for the first time that premature aging is associated with aldehyde-induced DNA damage." Dr Yasuyoshi Oka of Nagoya University in Japan, first author of the paper, noted.

  In this study, the scientists focused on the cellular damage caused by aldehyde-induced DNA-histone cross-linking (DPC). To do this, the team developed a high-throughput sequencing technique called DPC-seq.

  Combined with a series of experiments such as proteomics, the researchers found that aldehyde-induced DPCs occur centrally in active transcriptional regions, and that a previously unknown repair pathway is required for rapid and effective removal of DPCs, which involves the conventional transcription-coupled repair (TCR) pathway, as well as the VCP/p97 and proteasome.

  The researchers further confirmed the importance of the TCR pathway for repairing DNA damage in the presence of toxic aldehydes accumulation through animal experiments. To this end, they constructed a mouse model in which one of the gene mutations mimics the ALDH2gene defectthat makes humans blush when they drink alcohol. At the same time, these mice also had a mutation in theADH5gene, which means that they lacked another formaldehyde detoxification enzyme, so the toxic aldehydes were highly accumulated in the bloodstream, leading to a number of problems, including a short lifespan and abnormal haematopoiesis in the mice.

  Both the genetic defects and pathological manifestations in these mice are similar to AMED syndrome, a human genetic disease characterised by premature age ing. And in the animal model, when the researchers made their TCR pathway incomplete, the animals aged faster and developed more severe symptoms earlier.

  This result suggests that the pathological conditions seen in human patients with defective aldehyde scavenging mechanisms are likely to be related to aldehyde-induced DNA damage as well. The researchers hypothesise that the search for drugs capable of scavenging aldehydes will help provide candidate therapies for such patients.

  Although the experimental results described above mimic the genetic defects in patients with AMED syndrome, the researchers speculate that in healthy individuals, endogenous aldehyde-induced DNA damage may also play a role in the cellular aging process. And toxic aldehydes, in addition to coming from inadequate metabolism of alcohol, may also come from smoking, environmental pollution, and other pathways, all environmental factors that we can do our best to minimise or avoid.