Redox and mTOR-dependent regulation of plasma lamellar calcium influx controls the senescence-associated secretory phenotype

Cellular senescence has evolved as a protective mechanism to arrest growth of cells with oncogenic potential but is accompanied by the often pathologically deleterious senescence-associated secretory phenotype (SASP). Here we demonstrate an H2O2-dependent functional disruption controlling senescence-associated Ca(2+)homeostasis and the SASP. Senescent cells fail to respond to H2O2-dependent plasma lamellar Ca(2+)entry when compared to pre-senescent cells. Limiting exposure to senescence-associated H(2)O(2)restores H2O2-dependent Ca(2+)entry as well as transient receptor potential cation channel subfamily C member 6 (TRPC6) function. SA-TRPC6 and SASP expression is blocked by restoring Ca(2+)entry with the TRP channel antagonist SKF-96365 or by the mTOR inhibitors rapamycin and Ku0063794. Together, our findings provide compelling evidence that redox and mTOR-mediated regulation of Ca(2+)entry through TRPC6 modulates SASP gene expression and approaches which preserve normal Ca(2+)homeostasis may prove useful in disrupting SASP activity. Impact statement Through its ability to evoke responses from cells in a paracrine fashion, the senescence-associated secretory phenotype (SASP) has been linked to numerous age-associated disease pathologies including tumor invasion, cardiovascular dysfunction, neuroinflammation, osteoarthritis, and renal disease. Strategies which limit the amplitude and duration of SASP serve to delay age-related degenerative decline. Here we demonstrate that the SASP regulation is linked to shifts in intracellular Ca(2+)homeostasis and strategies which rescue redox-dependent calcium entry including enzymatic H(2)O(2)scavenging, TRP modulation, or mTOR inhibition block SASP and TRPC6 gene expression. As Ca(2+)is indispensable for secretion from both secretory and non-secretory cells, it is exciting to speculate that the expression of plasma lamellar TRP channels critical for the maintenance of intracellular Ca(2+)homeostasis may be coordinately regulated with the SASP.