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Cellular senescence has evolved as a protective mechanism to arrest growth of cells with oncogenic potential. While senescent cells have lost the ability to divide, they remain metabolically active and adapt a deleterious senescence associated secretory phenotype (SASP) central to the progression of several age-associated disease pathologies. The SASP is mechanistically regulated by the pro-inflammatory cytokine interleukin-1 alpha (IL-1α) whose expression and activity is responsive to the senescence associated (SA) oxidant production and the accompanying disruption of calcium (Ca2+) homeostasis. Using primary IMR-90 human fetal lung fibroblasts as a model of replicative senescence, we explored the molecular underpinnings facilitating increased Ca2+ entry in senescent cells. We establish that the redox-responsive Transient Receptor Potential TRPC6 channel is compromised due to desensitization owing to SA increases in steady state hydrogen peroxide (H2O2) production. SA dysregulation of Ca2+ is also accompanied by loss of response to H2O2-induced Ca2+ influx that can be rescued with catalase pre-treatments. Senescent cells are also insensitive to Ca2+ entry induced by hyperforin, a specific activator of TRPC6 that can be restored by catalase pre-treatments, further suggesting redox regulation of TRPC6 in senescence. Inhibition of TRPC6 channel activity restores ability of senescent cells to respond to peroxide-induced Ca2+ in addition to suppressing SASP gene expression. Furthermore, mammalian target of rapamycin (mTOR) signaling regulates SASP by means of modulating TRPC6 channel expression. Together, our findings provide compelling evidence that H2O2 and mTOR-mediated regulation of TRPC6 channel modulates SASP gene expression. As TRP channels emerge as targets of pharmacologic intervention for numerous disease pathologies, it is exciting to speculate that effect of TRP interventions may be attributed in part to inhibition of senescence and the SASP.

Cellular senescence has evolved as one of the protective mechanisms to arrest the growth of cells with oncogenic potential. While senescent cells lose the ability to divide, they remain metabolically active and adapt a senescence-associated secretory phenotype (SASP). The SASP is central to the progression of several age-associated disease pathologies perpetuated by inflammation. A key modulator of SASP is the pro-inflammatory cytokine interleukin-1 alpha (IL-1α) whose expression and activity is responsive to the senescence-associated (SA) oxidant production and the accompanying disruption of calcium (Ca2+) homeostasis. Members of the Transient Receptor Potential (TRP) channel family control cellular Ca2+ and are sensitive to activation by steady state hydrogen peroxide (ss-H2O2). This study aims at determining the molecular identity of the Ca2+ channel(s) that control the activity of the SASP regulator IL-1α. Using primary IMR-90 human fetal lung fibroblasts as a cellular senescence model, we have begun to explore the likely channel responsible for increased Ca2+ entry in senescent cells. We establish the idea that the redox-responsive TRPM2/TRPC5 channel activity is compromised during senescence due to desensitization by increased ss-H2O2 and TRPC6 channel activity is elevated to compensate for this loss of H2O2-responsive channel activity, thereby modulating SA dysregulation of Ca2+. We hypothesize that modification of this Ca2+ channel in the senescent cells can limit the downstream processing and regulation of IL-1α thereby reversing the SASP. This can establish a new paradigm of communication between the mitochondrial reactive oxygen species (ROS), cytosolic Ca2+ and nuclear IL-1α in senescence. Also, IL-1 α and TRPC6 have been shown to be independently regulated by mechanistic target of rapamycin (mTOR) signaling, a nutrient sensing pathway involved in regulation of aging processes. Overall, these studies identifying the TRPC6-mediated IL1α regulatory loop in senescence have the potential to identify new therapeutic approaches that limit the disease promoting properties of senescent cells without impairing their ability to defend against oncogenic insult.