Research Paper Volume 14, Issue 22 pp 8914—8926

Glutaminase inhibitors rejuvenate human skin via clearance of senescent cells: a study using a mouse/human chimeric model

Kento Takaya1, , Tatsuyuki Ishii1, , Toru Asou1, , Kazuo Kishi1, ,

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

Received: August 30, 2022       Accepted: November 7, 2022       Published: November 21, 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.


Skin aging caused by various endogenous and exogenous factors results in structural and functional changes to skin components. However, the role of senescent cells in skin aging has not been clarified. To elucidate the function of senescent cells in skin aging, we evaluated the effects of the glutaminase inhibitor BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl)ethyl sulfide) on human senescent dermal fibroblasts and aged human skin. Here, primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, ionizing radiation, and treatment with doxorubicin, an anticancer drug. Cell viability of HDFs was assessed after BPTES treatment. A mouse/human chimeric model was created by subcutaneously transplanting whole skin grafts from aged humans into nude mice. The model was treated intraperitoneally with BPTES or vehicle for 30 days. Skin samples were collected and subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, and histological analysis. BPTES selectively eliminated senescent dermal fibroblasts regardless of the method used to induce senescence; aged human skin grafts treated with BPTES exhibited increased collagen density, increased cell proliferation in the dermis, and decreased aging-related secretory phenotypes, such as matrix metalloprotease and interleukin. These effects were maintained in the grafts 1 month after termination of the treatment. In conclusion, selective removal of senescent dermal fibroblasts can improve the skin aging phenotype, indicating that BPTES may be an effective novel therapeutic agent for skin aging.


DMSO: Dimethyl sulfoxide; DIS: Doxorubicin-induced senescence; DMEM: Dulbecco’s modified Eagle’s medium; GLS1: Glutaminase 1; H&E: Hematoxylin and eosin; HDFs: Human dermal fibroblasts; IRIS: Ionizing radiation-induced senescence; KGA: Kidney-type glutaminase; MT: Masson’s trichrome; PBS: Phosphate-buffered saline; PCR: Polymerase chain reaction; PDL: Population doubling level; RS: Replicative senescence; RT-qPCR: Reverse transcription-quantitative polymerase chain reaction; SASP: Senescence-associated secretory phenotype; SA-β-Gal: Senescence-associated β-galactosidase; SAASPs: Skin aging-associated secreted proteins; VEGF: Vascular endothelial growth factor.