Beware! People who blush when drinking alcohol not only have a high risk of cancer but are also prone to premature aging!

The May Day holiday is about to begin, and many people have already arranged drinking parties. As the saying goes, "drinking occasionally is good for a while, but drinking all the time will lead to death." About 3 million people die from excessive drinking every year. Studies have shown that there is a close relationship between drinking and various types of cancer, cardiovascular disease, cirrhosis, dementia, infectious diseases (such as tuberculosis and pneumonia), and so on.
Some people will experience redness on their face or even their entire body after drinking. This is closely related to the action of two enzymes in the human body - alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). When the ALDH2 gene of some individuals is defective, they lack the ability to eliminate aldehydes, resulting in insufficient metabolism of alcohol (ethanol) by the liver. The toxic intermediate product acetaldehyde cannot be converted into non-toxic acetic acid, which accumulates in the body and causes redness of the skin.

Recently, Tomoo Ogi's team at Nagoya University in Japan published a research paper in the journal Nature Cell Biology, Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair. The study revealed that aldehydes are a metabolic byproduct associated with premature aging, and the induced DNA-protein crosslinks (DPC) interfere with gene replication and transcription, blocking important enzymes in cell proliferation and maintenance. Genetic defects in DPC repair and aldehyde clearance can lead to progeria. Mice lacking aldehyde clearance and transcription-coupled repair (TCR) pathways showed more severe symptoms of AMeD syndrome (aplastic anemia, intellectual disability, and dwarfism, etc.), and exhibited severe hematopoietic abnormalities and general weakness. This study proposed for the first time that there is a close connection between aldehyde-induced DNA damage and progeria, providing new insights into hereditary progeria and human anti-aging!

Research content and results

Previous studies have shown that the most common forms of DNA damage induced by aldehydes are DNA-interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs). These types of damage are particularly harmful, interfering with DNA replication and leading to cell death if not repaired.

The research team found that the simultaneous loss of ADH5 and ALDH2 genes can cause AMeD syndrome, a typical premature aging disease, leading to the accumulation of endogenous formaldehyde and further DNA damage, manifested as bone marrow failure (aplastic anemia), intellectual disability (mental retardation) and developmental defects (dwarfism), which are caused by the accumulation of endogenous formaldehyde and the overload of the DNA repair pathway caused by formaldehyde-derived DNA damage. Therefore, the research team speculated that there is a certain correlation between aldehydes and aging.

Furthermore, AMeDS patients display combined features of Fanconi anemia (FA) and Cockayne syndrome (CS), a progressive neurodegenerative disease associated with defects in transcription-coupled repair (TCR), suggesting that the defective DNA repair pathway is involved in the removal of aldehyde-induced damage from active genes.

Source: Nature Cell Biology

The results showed that aldehyde-induced DPCs occurred in active transcriptional regions, and that the removal of DPCs in transcriptional regions required traditional TCR factors and proteasomes, and that aldehyde-induced transcriptional blockade lesions could be effectively repaired by TCR. At the same time, the loss of Adh5 and Aldh2 function also led to a significant increase in DPC levels.

To understand the role of TCR in removing DPCs in mice, the research team constructed mice with physiological impairments in both aldehyde detoxification and TCR pathways, and found that these genetically defective mice had a significantly shorter lifespan and weighed less than normal mice. TCR deficiency exacerbated the AMeDS syndrome phenotype in mice and caused hematopoietic abnormalities.

Source: Nature Cell Biology

In summary, the symptoms of AMeDS were obvious in mice with impaired aldehyde clearance mechanisms, proving the clear correlation between the accumulation of endogenous aldehydes and premature aging diseases, confirming the initial speculation of the research team! Finding drugs that can clear aldehydes will help provide candidate therapies for patients with the human genetic disease AMED syndrome.

Research Prospects

This shows that the harm of alcohol to people should not be underestimated. In addition to the premature aging mentioned above, many previous studies have shown that people who easily blush when drinking should pay more attention to the harm of alcohol.
On January 25, 2023, a research team from Stanford University published a research paper in the journal Science Translational Medicine titled SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. The study showed that the ALDH2 gene mutation that causes flushing after drinking increases the risk of coronary artery disease by inducing endothelial cell (EC) dysfunction in the blood vessel wall. In addition, the FDA-approved drug SGLT2 inhibitor Empagliflozin (a type 2 diabetes drug) can prevent and treat EC dysfunction associated with ALDH2 gene mutations, safeguarding people's lives, health and safety!

Source: Science Translational Medicine

On May 6, 2020, a research team from the University of Tokyo published a research paper in the journal Science Advances titled Defined lifestyle and germline factors predispose Asian populations to gastric cancer. The study sequenced the genes of 531 gastric cancer patients and found that 70% of the patients carried ALDH2 gene mutations, and more than 90% of them were Asians. It also suggests that patients with ALDH2 gene mutations have a significantly increased incidence of gastric cancer even if they only drink a small amount of alcohol, which means that people who easily blush when drinking have a higher risk of cancer!

Source: Science Advances

In short, people who blush after drinking need to be vigilant and take it seriously. They may not be suitable for drinking at the table. For the sake of their life and health, try to drink less.

References:

[1] Oka, Y., Nakazawa, Y., Shimada, M. et al. Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01401-2
[2] Guo H, Yu X, Liu Y, et al. SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. Sci Transl Med. 2023;15(680):eabp9952. doi:10.1126/scitranslmed.abp9952
[3] Suzuki A, Katoh H, Komura D, et al. Defined lifestyle and germline factors predispose Asian populations to gastric cancer. Sci Adv. 2020;6(19):eaav9778. Published 2020 May 6. doi:10.1126/sciadv.aav9778