Research Paper Volume 14, Issue 20 pp 8167—8178

Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging

Kento Takaya1, , Toru Asou1, , Kazuo Kishi1, ,

  • 1 Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan

Received: May 20, 2022       Accepted: August 24, 2022       Published: September 7, 2022
How to Cite

Copyright: © 2022 Takaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzled-related protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.


DMEM: Dulbecco’s Modified Eagle Medium; ECM: extracellular matrix; MMPs: matrix metalloproteinases; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; SFRP4: secreted frizzled-related protein 4; SASP: senescence-associated secretory phenotype.