Tohoku University led group elucidates the molecular mechanism of how elaidic acid promotes aging and inflammation

It has been suggested by past epidemiological studies that industrially produced trans-fatty acids such as elaidic acid (EA) contained in some processed foods are risk factors for atherosclerosis, neurodegenerative diseases, and lifestyle-related diseases (diabetes, MASLD) associated with aging and inflammation. However, our understanding of the detailed molecular mechanisms of the onset and exacerbation of related diseases associated with trans-fatty acid intake is insufficient, and there is little scientific evidence regarding actual toxicity.

A research group led by Graduate Student Ryota Kojima, Associate Professor Yusuke Hirata, Associate Professor Emiko Sato, and Professor Atsushi Matsuzawa from the Graduate School of Pharmaceutical Sciences at Tohoku University, in collaboration with Associate Professor Kotarou Hama and Professor Kazuaki Yokoyama from Teikyo University Faculty of Pharmaceutical Sciences, Professor Ryo Takita from the University of Shizuoka School of Pharmaceutical Sciences, and Professor Takuya Noguchi from Iwate Medical University School of Pharmacy, discovered that EA, the most major trans-fatty acid, promotes cellular senescence and inflammation that occur during DNA damage. This is an important finding that will lead to the development of groundbreaking prevention and treatment strategies for trans-fatty acid-related diseases. The findings were published online in iScience.

The research group focused on the fact that cellular senescence and inflammation are commonly and closely involved in trans-fatty acid -related diseases in general. They pretreated cell lines such as U2OS (human osteosarcoma) with EA to incorporate it into the cells in advance, then caused DNA damage to induce cellular senescence. As a result, in the presence of EA, cellular senescence and the accompanying production of inflammation-promoting factors such as IL-1α, IL-6, and IL-8 were enhanced. This effect was not observed with oleic acid, which is a geometric isomer of EA, or with any of the four major trans-fatty acids other than EA contained in food, revealing that this is a specific effect of EA.

Detailed analysis revealed that during DNA damage, EA promotes the activation of the transcription factor NF-κB, which mainly contributes to the induction of expression of inflammation-related factors, and enhances the activation of kinase molecules TAK1 and IKK, which work upstream.

Therefore, the group hypothesized the involvement of the IL-1 receptor at the most upstream position of the TAK1/IKK/NF-κB pathway and focused on lipid rafts (microdomains) on the cell membrane that are considered important for its activation. In the presence of EA, IL-6/8 expression during ligand stimulation by IL-1α was increased, and pharmacological removal of lipid rafts suppressed the activation of IKK and NF-κB, confirming the contribution of the IL-1 receptor and lipid rafts. Furthermore, when lipid raft fractions were biochemically separated and lipid analysis was performed, it was confirmed that EA added to cells was actually efficiently incorporated into lipid raft fractions. In the presence of EA, the quantity of the IL-1 receptor in the same fractions was significantly increased.

From these results, it was revealed that EA is incorporated into lipid rafts, thereby accumulating IL-1 receptors within this region and enhancing NF-κB activation associated with IL-1 ligand stimulation to promote the production of IL-1α/6/8, elucidating a series of molecular mechanisms that promote cellular senescence and inflammation through a positive feedback mechanism.

Furthermore, when analyzing the impact of the presence or absence of EA in the diet on the pathological condition when MASLD was induced by feeding wild-type mice (C57BL/6J) a high-fat diet for 12 weeks, it was found that EA intake significantly increased the number of senescent cells in the liver and the expression of gene groups related to inflammation and liver fibrosis such as IL-1β and col1a1. In other words, it was confirmed at the mouse individual level that cellular senescence and inflammation in the liver are actually enhanced during MASLD onset with EA intake.

There are expectations that future progress in research on this topic, and the elucidation of the induction and promotion of cellular senescence and inflammation by trans-fatty acids, will lead to the development of and proposals for prevention and treatment strategies for related diseases.

Journal Information
Publication: iScience
Title: Elaidic acid drives cellular senescence and inflammation via lipid raft-mediated IL-1R signaling
DOI: 10.1016/j.isci.2025.113305