More on Janus Kinase Inhibitors as a Possible Treatment for Cellular Senescence

In recent months a number of studies on Janus kinases (JAK) have been published, focusing on their effects on senescent cells, inflammation, and stem cell activity. In animal studies JAK inhibitors seem to reduce the harmful activities of senescent cells, which leads to modest benefits in old individuals, though it is unclear as to the degree to which these treatments are removing senescent cells via programmed cell death versus merely altering their behavior. Reports in the research literature vary on this count, but lean towards modulation. Trying to alter the behavior of senescent cells is in my eyes a poor substitute for a definitive targeted elimination of those cells, but there is value in all sound demonstrations of cellular senescence as an important contribution to degenerative aging, as they increase support for the development of treatments that can measurably impact aging.

Researchers have taken what they hope will be the first step toward preventing and reversing age-related stem cell dysfunction and metabolic disease. "Our work supports the possibility that by using specific drugs that target senescent cells - cells that contribute to frailty and disease associated with age - we could stop human senescent cells from releasing toxic proteins that are contributing to diabetes and breakdowns in stem cells in older individuals."

Researchers found that human senescent fat cells release a protein called activin A that impairs the function of fat tissue stem cells and fat tissue. They discovered an activin A increase in the blood and fat tissue of the aged mice. Treatment with Janus kinase (JAK) inhibitor drugs in aged mice, equivalent to 80-year-old people, decreased the amounts of activin A and partially reversed the fat tissue insulin resistance that contributes to diabetes in old age. In aged mice that are engineered to express a drug-activated gene in their senescent cells (called INK-ATTAC mice) treatment triggering the gene removed senescent cells, decreased activin A and increased the proteins that promote insulin sensitivity and reduce diabetes. This paralleled effects of the JAK inhibitor in normal, naturally aged mice. "The treated animals had improved glucose and insulin tolerance tests, tests that indicate the severity of diabetes. Our work suggests that targeting senescent cells or their products could be a promising avenue for delaying, preventing, alleviating or treating age-related stem cell and tissue dysfunction and metabolic disease."


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