Surveillance of senescent cells

Cellular senescence basically entails the cessation of growth and is associated with a reduction in expression of growth-promoting genes and upregulation of cell cycle inhibitors. Additionally, changes are observed in the expression of secreted molecules involved in extracellular matrix production and immune surveillance.


At the molecular level, the senescence programme is governed by the interplay between the retinoblastoma Rb and p53 tumour suppressor networks, and DNA damage response. In culture, senescent cells can continue to grow indefinitely, but their fate in tissues is not well understood and seems to be cell-specific. For example, senescent melanocytes can remain in the skin throughout life while senescent liver cells get cleared by the immune system.


To further explore this phenomenon, scientists on the EU-funded 'Mechanisms of immune surveillance of senescent cells' (SENESCENCE CLEARANCE) project set out to investigate the role of the immune system in clearance of senescent cells. Researchers had previously shown that the presence of senescent cells within a tissue directly affects the local microenvironment. In the liver, the clearance of senescent cells takes place by natural killer (NK) cells, thereby limiting the emergence of fibrosis.


During the SENESCENCE CLEARANCE study, scientists were able to show that senescent cells express higher levels of ligands that are recognised by NK receptors. Clearance seems to be driven by granule exocytosis, and mice with defects in this process accumulate senescent cells and display more severe liver fibrosis. Research into the mechanism identified the decoy death receptor Dcr2 as an important determinant of resistance of senescent cells to apoptosis and NK-mediated cell death.


The role of the immune system in the clearance of senescent cells is not limited to NK cells. Researchers found that senescent cells also attract macrophages that in turn recognise and engulf senescent cells.


Taken together, findings from the SENESCENCE CLEARANCE project underscore the significance of immune surveillance in the clearance of senescent cells. Given the association of senescence with ageing and tumour onset, these results could form the basis for future anticancer therapies.