The chronic inflammation of aging is a major contribution to the onset and progression of age-related disease. The immune system reacts to forms of molecular damage and dysfunction characteristic of aging in a maladaptive way, and the long-term consequences are unfortunate. Short-term inflammation is necessary and important, needed in contexts ranging from infection to suppression of cancer to regeneration following injury. Sustained, unresolved inflammation is disruptive to tissue structure and function, however.
The biggest challenge in finding ways to suppress long-term inflammation is that it appears to use the same systems of regulation as short-term inflammation, and thus successful approaches not only sabotage undesirable inflammation, but also degrade the effectiveness of the immune system. If there is a way to work around this problem, we should all be very interested, as it could form the basis for therapies that reduce age-related inflammation without harming the necessary functions of the immune system.
Chronic inflammation occurs when the immune system is stuck in attack mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health. A new study identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection.
Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. The researchers confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.
The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.
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