“DNA damage is linked with aging phenotypes,” said Yasuyoshi Oka. “However, for the first time, we propose a relationship between aldehyde-derived DNA damage and premature aging.”
Aldehydes are harmful to our health because they are highly reactive with our DNA and proteins, forming DNA-protein crosslinks (DPCs) which block important enzymes involved in cell proliferation and maintenance processes leading to malfunction and aging. The team hypothesized that there might be a link between aldehydes and aging as those with premature aging disorders such as AMeD syndrome exhibit inadequate activity of enzymes like ALDH2 that break down these metabolic byproducts.
ALDH2 is also important to our response to alcohol. Our liver metabolizes the alcohol into aldehydes to be eliminated from the body, making ALDHA activity important for converting aldehydes into a non-toxic substance.
According to the researchers, focusing on DPCs caused by aldehydes using DPC sequencing to investigate the links between accumulation of aldehydes and DNA damage in those with premature aging diseases in a series of experiments revealed that the TCR complex VCP/p97 and the proteasome are involved in the removal of formaldehyde-induced DPCs in actively transcribed regions. This discovery was confirmed in mouse models lacking aldehyde clearance processes and the TCR pathway that resulted in worsened symptoms of AMeD syndrome and suggests an association between premature aging disease and the accumulation of aldehydes.
“By elucidating the mechanism by which DNA damage heals quickly, we have revealed part of the cause of genetic premature aging,” said Professor Tomoo Ogi of Nagoya University.
“Our research opens up new avenues for understanding the underlying mechanisms of premature aging diseases and offers potential targets for therapeutic intervention,” Oka said. “By elucidating the role of aldehydes in DNA damage and aging, we are paving the way for future studies aimed at developing novel treatments and interventions.”
“The development of therapeutic drugs has not progressed because we have not fully understood the causes of AMeD syndrome and Cockayne syndrome. This study suggests that the patient’s pathological condition is related to DPC derived from aldehydes generated within cells. These results are expected to help in the search for compounds that remove aldehydes, thus aiding in the formulation of therapeutic drug candidates,” added Oka.
The team believes that this work has implications extending beyond genetic diseases, suggesting that aldehyde-induced DNA damage may play a role in the aging process in healthy people as well. By identifying these byproducts as substances that contribute to aging a new light has been shed on the intricate connection between environmental factors and cellular aging which could have significant implications for human health and our lifespan.
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https://www.nagoya-u.ac.jp/researchinfo/result-en/2024/04/20240411-01.html
