Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease
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DOI：
10.1016/j.ebiom.2019.08.069
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发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Kirkland, James L.
中科院分区：
文献类型：
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作者：
Hickson, LaTonya J.;Prata, Larissa G. P. Langhi;Kirkland, James L.
背景资料：衰老细胞可释放导致炎症和功能障碍的因子，即衰老相关分泌表型（SASP），随着衰老和多种慢性疾病的病因部位而积累。包括达沙替尼和槲皮素（D+Q）的组合的Senolytics通过暂时禁用保护衰老细胞免受其自身凋亡环境的促存活网络来选择性地消除衰老细胞。在第一个senolytics的临床试验中，D+Q改善了特发性肺纤维化（IPF）患者的身体功能，IPF是一种致命的衰老相关疾病，但迄今为止，没有同行评议的研究直接证明senolytics可以减少人类的衰老细胞。在一项开放标签的1期初步研究中，我们对糖尿病肾病受试者口服D 100 mg和Q 1000 mg，持续3天（N = 9; 68.7 ± 3.1岁; 2名女性; BMI：33.9 ± 2.3 kg/m（2）; eGFR：27.0 ± 2.1 mL/min/1.73 m（2））。在完成衰老清除治疗之前和之后11天收集脂肪组织、皮肤活检和血液。衰老细胞和巨噬细胞/朗格汉斯细胞标志物和循环SASP factors assayed.Findings：D+ Q在11天内减少了脂肪组织衰老细胞的负荷，减少了p16（INK 4A）-andp 21（CIP 1）-表达细胞、衰老相关β-半乳糖苷酶活性细胞和复制潜力有限的脂肪祖细胞。被衰老细胞吸引、锚定和激活的脂肪组织巨噬细胞和冠状结构减少。皮肤表皮p16（INK 4A+）和p21（CIP 1+）细胞减少，循环SASP因子也减少，包括IL-1 α、IL-6和MMP-9和-12。解释：使用senolytics的“打了就跑”治疗，在D+Q的情况下，其具有消除半衰期
Background: 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.Methods: 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; 2female; BMI: 33.9 +/- 2.3 kg/m(2); eGFR: 27.0 +/- 2.1 mL/min/1.73m(2)). 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.Findings: D+ Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16(INK4A)-andp21(CIP1)-expressing cells, cells with senescence-associated beta-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 p16(INK4A+) and p21(CIP1+) cells were reduced, as were circulating SASP factors, including IL-1 alpha, IL-6, and MMPs-9 and - 12.Interpretation: "Hit-and-run" treatment with senolytics, which in the case of D+Q have elimination half-lives