Inflammation promotion by senescent cells: Discovery of involvement of "ACLY" through comprehensive gene analysis by Kumamoto University

A research group led by Appointed Assistant Professor Kan Etoh and Professor Mitsuyoshi Nakao from the Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics at Kumamoto University discovered ATP-citrate lyase, "ACLY," an enzyme that promotes inflammatory responses in senescent cells, using comprehensive gene analysis. They found that inhibiting ACLY ameliorates chronic inflammation associated with aging. Inhibition of this pathway is expected to serve as a method of regulating age-related chronic inflammation. The results were published in the online edition of Cell Reports on July 22.

After repeated cell divisions, many cells that make up the body undergo cellular senescence, gradually losing their functions and ceasing proliferation. While cellular senescence plays a role in preventing malignant transformation of cells, senescent cells secrete inflammatory proteins, promoting chronic inflammation and cancer cell growth. These characteristics are referred to as the senescence-associated secretory phenotype (SASP).

In response to this issue "senolytics" (the removal of senescent cells) with drugs has attracted attention. It has been reported that removal of senescent cells causes tissue fibrosis to fill in the gaps, resulting in functional decline. If cellular senescence and SASP can be controlled, it may be possible to regulate the rate of senescence. Previously, the research group has conducted research from the perspective of epigenetics and identified multiple factors involved in senescence in human fibroblasts. They have shown that mitochondrial metabolic function in senescent cells is markedly elevated by "RB tumor suppressor protein" and that "SETD8 methyltransferase," "NSD2 methyltransferase," and some other factors are involved in the prevention of cellular senescence.

In this study, the group found that ACLY levels increased in senescent cells, which are in a state of stable growth arrest, and that inhibition of ACLY in senescent cells resulted in strong suppression of the function of inflammatory protein genes. ACLY is a metabolic enzyme that synthesizes acetyl-CoA from citric acid in the cell and regulates cellular activity and gene function. The research group also found that treating aged mice with inhibitors of ACLY or BRD4 suppressed chronic inflammation by downregulating the interferon pathway mediated by STAT1, a transcription factor that is activated in the event of exposure to inflammatory proteins such as interferons.

Nakao said, "In senescent cells, ACLY synthesizes acetyl-CoA from citric acid, and we found that this acetyl-CoA is selectively used to activate the proinflammatory SASP genes. Since SASP in senescent cells promotes whole-body aging and the development of age-related diseases, inhibition of ACLY and BRD4 will lead to the realization of 'senostatics,' which retain senescent cells and selectively suppress SASP. Even if full restoration of age-related lesions is difficult to achieve, we hope to extend healthy life expectancy by decelerating the progression of senescence stages."

Journal Information
Publication: Cell Reports
Title: Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers
DOI: 10.1016/j.celrep.2024.114496