Summary Background Oxytocin (OT) is a neuropeptide hormone that has many beneficial biological effects, including protection against age‐related disorders. However, less is known about its role in intrinsic skin ageing, which is accelerated by an increase in senescent cell fraction in skin tissue. Objectives To investigate the novel function and the underlying mechanism of OT in preventing cellular senescence in normal human dermal fibroblasts (NHDFs) isolated from the skin of female donors of different ages. Methods NHDFs from young and old donors were exposed to conditioned medium from senescent or control NHDFs in the presence or absence of 10 nmol L−1 OT for 3 days, and were continuously subcultured for 12 days. Subsequently, various age‐associated signs of senescence including decreased proliferation rate, elevated p16 and p21 levels, and positivity for senescence‐associated β‐galactosidase expression were examined. Results We found that OT suppressed senescence‐associated secretory phenotype‐induced senescence in NHDFs, and its effect depended on the age of the donor's NHDFs. The inhibitory effects of OT required signalling by OT receptor‐mediated extracellular signal‐regulated kinase/Nrf2 (nuclear factor erythroid 2‐related factor 2). The age‐dependent antisenescence effects of OT are closely related to hypermethylation of the OT receptor gene (OXTR). Conclusions Our findings bring to light the role of OT in the prevention of skin ageing, which might allow development of new clinical strategies. What's already known about this topic? Senescent keratinocytes and fibroblasts accumulate with age in the skin and contribute to the loss of skin function and integrity during ageing. Senescent cells secrete senescence‐associated secretory phenotype (SASP), which includes the release of proinflammatory cytokines such as interleukin (IL)‐6 and IL‐1, chemokines, extracellular matrix‐remodelling proteases and growth factors. The neuropeptide oxytocin (OT) and its receptor (OXTR) have protective effects against various age‐related disorders. What does this study add? OT suppressed SASP‐induced cellular senescence in normal human dermal fibroblasts (NHDFs), depending on the age of the NHDFs’ donor. The inhibitory effects of OT on cellular senescence required OXTR‐mediated phosphorylation of extracellular signal‐regulated kinase, which enhanced nuclear localization of Nrf2, a vital factor in the antioxidant defence system. The age‐specific antisenescent effects of OT were closely related to hypermethylation of OXTR. What is the translational message? Our results suggest that OT and OXTR agonists could be clinically promising agents for the improvement of age‐associated skin ageing, especially in women.

Summary Intrinsic skin aging is skin aging affected by natural factors within the body, such as hormones, rather than by external factors like UV light or smoking. Skin ageing causes the appearance of wrinkles, skin sagging and reduced elasticity. Like elsewhere in the body, skin ageing involves an increase in the proportion of cells undergoing cellular senescence (a type of deterioration due to age). Senescent skin cells called dermal fibroblasts have several characteristics that are different to cells that are not senescent, including having what is known as a senescence‐associated secretory phenotype (SASP). Oxytocin (OT) is a neuropeptide hormone that has many beneficial effects in the body, including protection against age‐related disorders. However, less is known about the role of OT in intrinsic skin aging. The authors looked into the role of oxytocin in prevention against senescence in skin cells called normal human dermal fibroblasts (NHDFs), taken from female donors of different ages. They found that OT suppressed SASP‐induced senescence in NHDFs derived from young but not old female donors. The authors were also able to learn more about the processes within the body by which OT suppresses SASP and why it affects younger women differently to older women. Their results demonstrate that oxytocin may be effective in the prevention of skin aging.