Testing a Glutaminase Inhibitor to Clear Senescent Cells in Skin Models

Glutaminase inhibitors can potentially eliminate senescent cells from aged tissues, another in the growing list of categories of senolytic compound. Researchers here test the proposition in various skin models, some involving immunodeficient mice hosting human skin grafts. At this point there are so many different senolytics that studies should start to focus on comparing efficacy. Where there is data to compare directly, development efforts conducted over the last decade have so far failed to greatly improve on the dasatinib and quercetin approach, the first senolytic treatment tested in mice and humans. It is likely that some of the companies developing novel senolytics can do considerably better, but that data is not yet available for review.

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.

Link: https://doi.org/10.18632/aging.204391