Blocking the citrate transporter reduced inflammatory secretion by senescent cells in aged mice
Blocking the citrate transporter reduced inflammatory secretion by senescent cells in aged mice
On 29 July, Nature published a study of a metabolic step that helps senescent cells activate inflammatory genes. After three months of CTPI2 treatment, aged mice showed fewer signs of inflammation and better measures of healthspan, including health and physical function.
A senescent cell stops dividing after damage or severe stress but remains in the tissue. Many of these cells release SASP, an inflammatory mixture of cytokines, growth factors, and enzymes. SASP changes the environment around the cell and affects how neighboring cells function. As these cells accumulate with age, their secretions help sustain inflammation in tissues.
Mitochondrial DNA and RNA can enter the cytosol, the fluid inside the cell. The cell interprets these molecules as signs of infection and activates proteins that initiate inflammatory gene expression. SASP requires another step: the genes must become accessible for transcription.
In the study by Hélène Martini's group, the researchers traced this step from the mitochondria to chromatin. Mitochondria produce citrate, and the protein SLC25A1 transports it into the cytosol. The cell then uses citrate to produce acetyl-CoA. This molecule is added to histones, the proteins around which DNA is packaged, making the DNA near SASP genes more accessible. The inflammatory signal can then reach these genes and activate the secretion of inflammatory molecules.
In cell models, CTPI2 blocked SLC25A1, reduced histone acetylation near SASP genes, and lowered their activity. Adding acetate, which cells can use to produce acetyl-CoA, restored part of the inflammatory program. Citrate export supplied the cell with the chemical resource needed to activate inflammatory genes.
The researchers then administered CTPI2 to aged mice for three months. Inflammatory signals declined in the blood, liver, and heart. Cardiomyocyte hypertrophy, which is the enlargement of heart muscle cells, also decreased in cardiac tissue. Mice treated with CTPI2 also showed better measures of healthspan.