| Sumario: | Purpose Cellular senescence refers to the cessation of cell proliferation that can be triggered by endogenous and exogenous stimuli, such as telomere dysfunction, DNA damage, and oncogenic gene expression (Di Micco et al, 2021). Senescent cells release senescent-associated secretory phenotype (SASP), which turns neighboring normal cells into senescent cells. As the accumulation of senescent cells compromises tissue repair and function, cellular senescence eventually leads to tissue aging and aging-related chronic diseases, including type 2 diabetes. Therefore, killing the senescent cells (senolytics) or reversing the senescent cells to young cells (senomorphics) can prevent or alleviate aging and aging-associated diseases (Niedernhofer and Robbins 2018). Recently, previous studies showed the reduction in senescent cells in adipose tissue attenuates insulin resistance in high-fat diet (HFD)-fed obese mice, suggesting that targeting cellular senescence in adipose tissue could be the potential treatment for type 2 diabetes (Smith et al 2021). Currently, however, there is no clinically available effective senotherapy. In our study, we aimed to find a novel senotherapy for adipose tissue aging and insulin resistance. Method We examined 2,150 clinically available compounds for their senolytic or senomorphic effect in human dermal fibroblast (HDF) by using cell toxicity or senescent-associated beta-galactosidase staining, respectively. Among the 10 compounds which were found to have a senolytic or senomorphic effect in HDF, one compound also attenuated senescence in human preadipocytes and 3T3-L1 adipocytes. The effects of the new senolytic agent (HT) on adipose tissue aging and insulin sensitivity were examined in high-fat diet-fed obese mice and aged mice. Results and Discussion HT attenuated weight gain and reduced fat mass in obese mice even though it did not affect food intake. It reduced adipose tissue aging both in obese mice and aged mice, which was followed by a reduction in large-sized adipocytes, the number of crown-like structures, and the levels of inflammatory cytokines. HT improved glycemic control and insulin resistance. It also reduced adipose tissue aging in human subcutaneous adipose tissue ex vivo. Thus, these results suggest that we have found a novel senolytic agent that may be a potential therapeutic for type 2 diabetes.
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