Senescent cells survive with low levels of a fatty acid, DGLA: adding it selectively kills them in cell culture and reduces senescence markers in fat and liver tissue in old mice
Senescent cells survive with low levels of a fatty acid, DGLA: adding it selectively kills them in cell culture and reduces senescence markers in fat and liver tissue in old mice
On November 2, Cell published a study by Christopher Wiley’s group at Tufts University on DGLA, dihomo-gamma-linolenic acid.
A damaged cell can die, or it can stop dividing and remain in the tissue, a state called cellular senescence. Senescent cells accumulate with age and release inflammatory molecules. One form of cell death is ferroptosis: iron drives a chain reaction that oxidizes membrane lipids, causing the membrane to rupture. What determines whether a cell undergoes senescence or ferroptosis has been unclear. The starting point was Wiley’s 2021 study: senescent cells convert polyunsaturated fatty acids (those with several double bonds) into signaling lipids that reinforce the arrest of cell division. The team has now examined what happens to the fatty acids themselves in cell membranes.
In cultured senescent human connective tissue cells, membrane levels of polyunsaturated fatty acids increased overall, while levels of one, DGLA, decreased. DGLA is an intermediate in a series of fatty acid conversions: the enzyme FADS2 initiates the pathway leading to DGLA, and FADS1 converts it into arachidonic acid. Across five methods of inducing senescence, the balance between the two enzymes shifted toward FADS1. To test the role of DGLA, the researchers added it to the culture medium: after three days, senescent cells died while normal cells survived. Other omega-6 and omega-3 fatty acids at the same dose showed no such selectivity. An FADS1 inhibitor, which prevents DGLA from being converted into arachidonic acid, also selectively killed senescent cells.
The added DGLA killed senescent cells through ferroptosis: inhibitors of other forms of cell death failed to rescue them, whereas compounds that bind iron or suppress lipid oxidation did. DGLA had previously been shown to induce ferroptosis in the worm C. elegans and in human cancer cells.
Senescent cells take up DGLA more actively: when the authors suppressed the fatty acid transporter CD36, DGLA stopped killing them. These cells also show features of ferroptosis: they have more free iron, higher expression of genes encoding lipoxygenases, enzymes that oxidize lipids, and low levels of ongoing membrane lipid oxidation. The authors suggest that this oxidation may be held in check by elevated levels of GPX4, an enzyme that neutralizes lipid peroxides.
On this basis, the authors propose that senescent cells exist “in a state of subferroptotic stress,” close to the threshold for cell death.
Mice aged 22–24 months received DGLA for five consecutive days. Two weeks later, fat and liver tissue showed less staining for β-galactosidase, a marker of senescent cells. Fat tissue also showed lower expression of p21 and p16, genes that maintain the arrest of cell division, and of genes encoding inflammatory molecules. In the liver, senescence markers decreased in males; in a set of experiments in which males had poorer blood test results at baseline, their measures of liver and kidney function also improved. Wiley is listed as an inventor on patent applications for using DGLA to eliminate senescent cells.
In Kuopio, Finland, researchers examined subcutaneous fat from 131 women and 54 men with obesity. People with a FADS1 gene variant that reduces the conversion of DGLA into arachidonic acid (the CC genotype) had lower p21 gene expression in fat tissue. The association was statistically significant in women and in the combined group.
Paul Robbins’s group at the University of Minnesota found another route to ferroptosis in senescent cells. Screening fatty acids in mouse cells, the researchers found that conjugated fatty acids (in which double bonds alternate with single bonds) killed senescent cells, while DGLA had no effect.