Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice

Abstract

Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging‐associated tumorigenesis induced by ultraviolet B

“…Furthermore, the knockdown of TRPC7 inhibited UVB‐induced p53 expression in keratinocytes (Figure e–g), which was corroborated by our observation that the UVB‐induced activation of the p53 pathway was reduced in TRPC7 +/− and TRPC7 −/− mice (Figure i). In addition, extracellular Ca 2+ influx is known to induce cyclooxygenase‐2 (COX‐2) expression, which increases p53 pathway activation and promotes the aging process (Hsu et al, ; Kim et al, ). We found that after UVB exposure, the high levels of COX‐2 protein expression observed in the epidermis of wild‐type mice were decreased to minimal levels in TRPC7 +/− and TRPC7 −/− mice (Figure h).…”

Aspirin ameliorates the long‐term adverse effects of doxorubicin through suppression of cellular senescence

“…Aspirin is thought to exert its effects through inhibition of COX enzymes . In addition, we previously have reported that the inducible, transgenic expression of COX2 causes accumulation of senescent cells and early aging phenotypes in adult mice . Therefore, we focused our investigation on the role of COX2 in DOX‐induced cellular senescence.…”

“…70 Finally, we recently have reported that inducible COX2 expression in adult mice promotes senescence and early aging. 30 We have previously reported that genetic deletion or pharmacological inhibition of COX2, but not COX1, suppresses DOX-induced accumulation of p53. 18 In addition, our current data show that aspirin suppresses DOX-induced p53 accumulation in normal human fibroblasts and WT MEFs.…”

“…Third, COX2 expression is induced by virtually all known environmental gerontogens such as arsenic, benzene, cigarette smoke, UV, chemotherapy, and psychological stress, whereas caloric restriction, which is known to suppress the aging process, decreases COX2 expression and activity . Finally, we recently have reported that inducible COX2 expression in adult mice promotes senescence and early aging …”

“…29 In addition, we previously have reported that the inducible, transgenic expression of COX2 causes accumulation of senescent cells and early aging phenotypes in adult mice. 30 Therefore, we focused our investigation on the role of COX2 in DOX-induced cellular senescence. We first analyzed the levels of COX2 in 16-to 18-week-old mice treated with DOX at their juvenile stage.…”