Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics.

Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.

Gao Y ，Wu T ，Tang X ，Wen J ，Zhang Y ，Zhang J ，Wang S ... -  《-》

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.

Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

Hickson LJ ，Langhi Prata LGP ，Bobart SA ，Evans TK ，Giorgadze N ，Hashmi SK ，Herrmann SM ，Jensen MD ，Jia Q ，Jordan KL ，Kellogg TA ，Khosla S ，Koerber DM ，Lagnado AB ，Lawson DK ，LeBrasseur NK ，Lerman LO ，McDonald KM ，McKenzie TJ ，Passos JF ，Pignolo RJ ，Pirtskhalava T ，Saadiq IM ，Schaefer KK ，Textor SC ，Victorelli SG ，Volkman TL ，Xue A ，Wentworth MA ，Wissler Gerdes EO ，Zhu Y ，Tchkonia T ，Kirkland JL ... -  《EBioMedicine》

Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated β-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

Tanaka T ，Urata Y ，Harada M ，Kunitomi C ，Kusamoto A ，Koike H ，Xu Z ，Sakaguchi N ，Tsuchida C ，Komura A ，Teshima A ，Takahashi N ，Wada-Hiraike O ，Hirota Y ，Osuga Y ... -  《-》

The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency.

Xu Z ，Takahashi N ，Harada M ，Kunitomi C ，Kusamoto A ，Koike H ，Tanaka T ，Sakaguchi N ，Urata Y ，Wada-Hiraike O ，Hirota Y ，Osuga Y ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263.

Abdelgawad IY ，Agostinucci K ，Ismail SG ，Grant MKO ，Zordoky BN ... -  《Cells》