Researchers at UC San Francisco recently found that activating invariant natural killer T (iNKT) cells eliminated inflammatory senescent cells associated with chronic diseases in vivo. In the study, obese mice showed improved glucose control and mice with pulmonary fibrosis had decreased lung fibrosis and increased survival. This research paves the way for anti-senescence therapies that target iNKT cells and their mechanism of activation.
Senescent cell accumulation linked with age-related diseases
The accumulation of senescent cells in the body is linked with age-related diseases, including diabetes and pulmonary fibrosis. In a healthy state, iNKT cells function as a surveillance system, eliminating cells the body senses as foreign, including senescent cells. These cells have irreparable DNA damage, do not die, and emit substances that damage nearby healthy cells, leading to inflammation. iNKT cells become less active with age, obesity and other factors that contribute to chronic disease.
For anti-senescence therapies, activating iNKT cells is an appealing technique for two reasons. First, iNKT cells share a unique receptor, meaning they can be activated without priming other immune cells. Second, iNKT cells don’t need to be deactivated. After a period of activity, they become dormant on their own.
“Using iNKT-targeted therapy can piggyback on their exquisite built-in specificity,” said Anil Bhushan, PhD, a professor at the Diabetes Center at UCSF and senior author of a paper on the study published in Med. Mallar Bhattacharya, MD, an associate professor of medicine at UCSF who treats patients with lung disease, is also an author of the paper.
Lipid antigens activate iNKT cells for anti-senescence therapy
The research team found they could remove senescent cells by using lipid antigens to activate iNKT cells. Obese mice injected with alpha-galactosylceramide (GalCer) showed improved glucose control and reduction of senescent cells to a level like that of lean mice. Activating iNKT cells in the mice with damaged lungs reduced the accumulation of senescent cells in their lungs, decreased lung fibrosis and improved survival.
Activated human iNKT cells target senescent lung fibroblasts
To determine whether iNKT cells can act directly on senescent cells in humans, the researchers generated iNKT cells from a healthy human donor, cultured human lung fibroblasts and treated them to induce senescence. The activated human iNKT cells were preferentially cytotoxic to senescent lung fibroblasts. The glycolipid GalCer, which was again used to activate the iNKT cells, is well tolerated in humans and has minimal side effects.
“I think this is a potential immune therapy for senescence and fibrosis,” Bhattacharya said.
If the method proves successful, it could provide an alternative to senolytic therapies, which have been the primary approach to eliminating inflammatory senescent cells associated with chronic diseases. Senolytics can target non-senescent cells and cause serious side effects. Activated iNKT cells target only senescent cells and return to a dormant state, preventing extensive cell destruction.
UCSF Medical Center is ranked No. 6 in the nation for diabetes and endocrinology and No. 11 in the nation for pulmonology and lung surgery by U.S. News & World Report’s 2021-2022 Best Hospitals survey.
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