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October 27, 2024
Kumamoto, Japan—As Japan’s population ages at an unprecedented rate, researchers are increasingly focused on extending not just lifespan but “healthspan”—the years of life spent in good health. In a groundbreaking study, a research team at Kumamoto University has identified ATP-citrate lyase (ACLY) as a key enzyme in driving chronic inflammation associated with aging, revealing a new strategy for tackling age-related diseases and promoting healthier aging.
The researchers targeted “cellular senescence,” a process where aging cells stop dividing but remain active, often becoming a source of chronic inflammation. Known as the senescence-associated secretory phenotype (SASP), these cells release inflammatory proteins that accelerate diseases like dementia, diabetes, and atherosclerosis. The Kumamoto team’s discovery that ACLY plays a crucial role in activating SASP opens the door to new interventions against age-related inflammation.
Using advanced sequencing and bioinformatics, researchers analyzed human fibroblasts—cells widely present throughout the body—to understand how ACLY drives inflammation in senescent cells. They found that inhibiting ACLY, either genetically or through inhibitors, significantly lowered the expression of inflammation-related genes, thereby reducing the harmful inflammatory environment typically found in aged tissues.
The ACLY-BRD4 Pathway and Inflammation Control
A further breakthrough came when researchers examined the ACLY-BRD4 pathway, revealing that ACLY-derived acetyl-CoA alters histones, proteins around which DNA wraps, allowing the chromatin reader BRD4 to activate inflammatory genes. By targeting this ACLY-BRD4 pathway in aged mice, they successfully suppressed inflammation responses, underscoring ACLY inhibitors’ potential in reducing chronic inflammation while promoting healthy aging.
This study not only sheds light on the fundamental mechanisms of aging but also introduces a promising therapeutic strategy for age-related diseases. By focusing on cellular pathways rather than removing aging cells, these findings pave the way for therapies that could mitigate the negative effects of aging on cellular health, potentially extending healthy lifespan.
Funding and Support
This research was supported by the Japan Society for the Promotion of Science, the Coalition of Universities for Research Excellence Program (CURE), Murakami Farm Co., Ltd., and the Inter-University Research Network for High Depth Omics of the Institute of Molecular Embryology and Genetics (IMEG) at Kumamoto University.
For more details, refer to the full study published in Cell Reports: Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers by Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, and Mitsuyoshi Nakao, July 22, 2024. DOI: 10.1016/j.celrep.2024.114496.
