ACLY is crucial for the establishment and maintenance of pro-inflammatory SASP. The ACLY-BRD4 axis improves the inflammatory response linked to aging. Therefore, inhibition of the ACLY-BRD4 axis contributes to creating the pro-inflammatory microenvironment in senescent cells. Credit: Mitsuyoshi Nakao, Kan Etoh, Kumamoto University
A team from Kumamoto University has made a discovery that could help promote healthy aging. As the world’s population ages, Japan’s aging population in particular is growing at an unprecedented rate, making it crucial to increase healthy life expectancy rather than just life expectancy.
Research focuses on cellular senescence, a process by which cells stop dividing and enter a state associated with chronic inflammation and aging. This cellular state, known as senescence-associated secretory phenotype (SASP), involves the secretion of inflammatory proteins that accelerate aging and diseases, such as dementia, diabetes, and atherosclerosis. The article is published in the journal Cell Reports.
Researchers discovered that ATP-citrate lyase (ACLY), an enzyme involved in converting citrate to acetyl-CoA, plays a critical role in activating SASP. This discovery was made using advanced sequencing and bioinformatics analyzes of human fibroblasts, a cell type found throughout the body.
They demonstrated that blocking ACLY activity, either genetically or using inhibitors, significantly reduced the expression of genes linked to inflammation in aging cells. This suggests that ACLY is a crucial factor in maintaining the pro-inflammatory environment in aged tissues.
Additionally, the study found that ACLY-derived acetyl-CoA modifies histones, proteins around which DNA wraps, allowing the chromatin drive BRD4 to activate inflammatory genes. By targeting the ACLY-BRD4 pathway, researchers were able to suppress inflammatory responses in aged mice, highlighting the potential of ACLY inhibitors in controlling chronic inflammation while maintaining healthy aging.
This discovery opens new avenues for developing treatments that specifically target harmful aspects of aging cells without suppressing them, providing a promising strategy for managing aging and age-related diseases. The research provides a springboard toward therapies that can control cellular aging, thereby promoting longer, healthier lives.
More information:
Kan Etoh et al, Citrate metabolism controls the senescent microenvironment via remodeling of pro-inflammatory activators, Cell Reports (2024). DOI: 10.1016/j.celrep.2024.114496
Provided by Kumamoto University
Quote: Cellular senescence research identifies key enzyme to promote healthy aging (October 18, 2024) retrieved October 18, 2024 from
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