New tricks for dealing with old cells?

J. Campisi
Lawrence Berkeley National Laboratory, Berkeley, CA

Cellular senescence is a crucial tumor suppressive mechanism that prevents the proliferation of cells at risk for neoplastic transformation. Numerous potentially oncogenic stimuli can induce a senescence response, which causes cells to enter a stable and essentially irreversible growth arrested state. Senescent cells are metabolically active and secrete myriad inflammatory cytokines, growth factors and other molecules that can alter the local tissue microenvironment. Senescent cells have been shown to accumulate with age and at sites of age-related pathologies. There is mounting evidence that senescence-associated secretory phenotype may plan a causative role in age-related decrements in tissue structure and function, and in the etiology or promotion of several age-related diseases. Can senescent cells be eliminated from tissues? We find that senescent cells are targeted for clearance by the innate immune system, particularly natural killer cells.

However, some senescent cells can escape immune killing by secreting very high levels of matrix metalloproteinases (MMPs). These enzymes likely destroy the ligand-receptor interactions that are needed for killing by natural killer cells. Moreover, the killing of senescent cells can be greatly enhanced by MMP inhibitors, which therefore hold promise for improving the clearance of senescent cells from aged or diseased tissues. We also find that the senescence-associated secretion of inflammatory cytokines is dependent on continuous DNA damage signaling, particularly signaling initiated by the ATM protein kinase. Ablation of ATM kinase activity by RNA interference markedly reduces inflammatory cytokine secretion, suggesting that ATM inhibition might also hold promise for reducing local inflammation caused by senescent cells.

Keywords: Aging, Cancer, DNA damage signaling, Inflammation, Matrix metalloproteinases