Key Enzyme in Aging Cells to Promote Healthy Aging Has Been Identified
A team at Kumamoto University has made a groundbreaking discovery in the field of aging and inflammation. Japan’s aging population is growing at an unprecedented rate, making it crucial to extend healthy lifespans rather than just lifespans. The research focuses on “cellular senescence,” a process where cells stop dividing and enter a state associated with chronic inflammation and aging. This cellular state, known as the senescence-associated secretory phenotype (SASP), involves the secretion of inflammatory proteins that accelerate aging and disease, such as dementia, diabetes, and atherosclerosis.The researchers found 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 analyses on human fibroblasts, a type of cell found throughout the body. They demonstrated that blocking ACLY activity, either genetically or with inhibitors, significantly reduced the expression of inflammation-related genes in aging cells. This suggests that ACLY is a crucial factor in maintaining the pro-inflammatory environment in aged tissues.
Furthermore, the study revealed that ACLY-derived acetyl-CoA modifies histones, proteins that DNA wraps around, allowing the chromatin reader BRD4 to activate inflammatory genes. By targeting the ACLY-BRD4 pathway, the researchers were able to suppress inflammation 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 the harmful aspects of aging cells without removing them, offering a promising strategy for managing aging and age-related diseases. The research provides a stepping stone toward therapies that can control cellular aging, promoting longer, healthier lives.
Image Title: Involvement of ATP-citrate lyase (ACLY) in the pro-inflammatory senescence-associated secretory phenotype (SASP) in senescent cells.
Image Caption: ACLY is crucial for establishing and maintaining the pro-inflammatory SASP. The ACLY-BRD4 axis enhances the aging-related inflammatory response. Therefore, inhibiting the ACLY-BRD4 axis helps create the pro-inflammatory microenvironment in senescent cells.
Image Caption: ACLY is crucial for establishing and maintaining the pro-inflammatory SASP. The ACLY-BRD4 axis enhances the aging-related inflammatory response. Therefore, inhibiting the ACLY-BRD4 axis helps create the pro-inflammatory microenvironment in senescent cells.
| Authors |
Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, and Mitsuyoshi Nakao* |
| Title of original paper |
Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers |
| Journal | Cell Reports |
| DOI | 10.1016/j.celrep.2024.114496 |