Researchers have found how immune cells naturally clear the body of senescent cells, which could potentially be harnessed to treat age-related diseases.
When senescent cells accumulate within tissues, they can drive the progression of many chronic diseases. Although the use of senolytic drugs to remove senescent cells has emerged as a promising therapeutic approach, these drugs have ubiquitous targets which hinders their application due to the serious side effects. Our endogenous immune surveillance system is able to limit the build-up of senescent cells in healthy tissue. When the system fails to efficiently recognise and target these cells, senescent cells begin to accumulate. The exact identity of the cells that mediate senescent cell clearance in vivo is unclear.
Immune surveillance mechanism
In this study, published in Cell, researchers identified a class of lipid-activated T cells – invariant natural killer T cells (iNKTs). These cells are involved in the removal of pathologic senescent cells. The frequency and function of iNKTs declines with age. However, the link between this decrease and an increase in senescent cells during ageing or disease has not been explored. Here, researchers used two disease models in which senescent cells accumulate to test whether activation of iNKTs is sufficient to eliminate these cells in vivo. The two models included high-fat diet mice and mice treated with bleomycin.
The team found that activation of iNKT cells with prototypical glycolipid antigen alpha-galactosylceramide (αGalCer) resulted in a reduction of senescent cells in high-fat diet mice. It also improved glucose control. This was also seen in mice injured by bleomycin. Activation of iNKT cells led to limited accumulation of senescent cells, decreased lung fibrosis and improved survival. Culture experiments showed that the direct cytotoxic activity of iNKT cells to senescent cells was also conserved in human cells.
Overall, these findings describe how lipid antigen presentation to activate iNKT cells can constitute an endogenous surveillance system that can be manipulated to clear senescent cells. As a result, these cells could pave the way for a potential immune therapy for senescence and fibrosis.
Image credit: By kjpargeter – freepik