Elevated skin senescence in young mice causes delayed wound healing.

Although there is growing evidence that cellular senescence influences wound healing, a clear understanding of how senescence can be beneficial and/or detrimental to wound healing is unknown. Wound healing may also be influenced by the baseline tissue senescence, which is elevated in aging and chronic wounds, both of which have significant healing delays. To study the effects of skin senescence on wound healing, we developed an elevated skin senescence model based on the subcutaneous transfer of irradiated fibroblasts into young 8-week-old wild-type C57BL/6 male mice. This senescent cell transfer significantly increased skin senescence levels compared to control transfers of non-irradiated fibroblasts. There was an increased presence of SA-ß-Gal- and p21-positive senescent cells throughout the skin. Furthermore, the entire skin showed significantly elevated gene expression of senescence (p16, p21) and SASP markers (IL-6, MCP-1, MMP-3, MMP-9, and TGF-ß). Subsequent wound healing in the skin with elevated senescence was markedly delayed and had similar kinetics to naturally aged 2-year-old mice. After the wounds had healed, the skin developed persistently elevated senescence. Our results demonstrate that states of elevated skin senescence can delay wound healing and result in sustained senescence after healing. Therefore, the accumulation of senescent cells in aged skin or chronic wounds may be a driver of delayed healing and can be considered a potential target to improve healing.

An Insight into Aging, Senescence, and Their Impacts on Wound Healing.

Cellular senescence has been found to have beneficial roles in development, tissue regeneration, and wound healing. However, in aging senescence increases, and the ability to properly repair and heal wounds significantly declines across multiple tissues. This age-related accumulation of senescent cells may cause loss of tissue homeostasis leading to dysregulation of normal and timely wound healing processes. The delays in wound healing of aging have widespread clinical and economic impacts, thus novel strategies to improve wound healing in aging are needed and targeting senescence may be a promising area.