HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice,iScience

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HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice
iScience ( IF 4.6 ) Pub Date : 2023-12-12 , DOI: 10.1016/j.isci.2023.108681
Alessandra Tammaro ₁ , Eileen G Daniels _{2,

3} , Iman M Hu _{2,

3} , Kelly C 't Hart _{2,

3,

4,

5} , Kim Reid ₆ , Rio P Juni _{4,

5} , Loes M Butter ₁ , Goutham Vasam ₆ , Rashmi Kamble ₂ , Aldo Jongejan ₇ , Richard I Aviv _{8,

9} , Joris J T H Roelofs _{1,

10} , Eleonora Aronica ₁₁ , Reinier A Boon _{4,

5} , Keir J Menzies ₆ , Riekelt H Houtkooper _{2,

3,

5} , Georges E Janssens _{2,

3}

Affiliation

Amsterdam UMC location University of Amsterdam, Department of Pathology, Amsterdam Infection & Immunity, Amsterdam, the Netherlands.
Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Department of Biology, University of Ottawa, Ottawa, ON, Canada.
Deptartment of Epidemiology & Data Science (EDS), Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Department of Medical Imaging, The Ottawa Hospital, 1053 Carling Ave, Ottawa, ON K1Y 4E9, Canada.
Department of Radiology, University of Ottawa, Ottawa, ON, Canada.
Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions. In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.

中文翻译：

HDAC1/2 抑制剂治疗改善老年小鼠多器官系统

衰老会增加患年龄相关疾病的风险，从而带来大量的医疗保健和个人成本。在药理学上针对基本的衰老机制可以促进健康衰老并降低这种疾病的易感性。在这项工作中，我们采用基于转录组的药物筛选来鉴定模拟长寿命遗传干预转录特征的化合物。我们发现了化合物 60 （Cmpd60），一种选择性组蛋白脱乙酰酶 1 和 2 （HDAC1/2）抑制剂，模拟了多种长寿干预措施。在使用各种细胞和老年小鼠模型进行广泛的分子、表型和生物信息学评估中，我们发现 Cmpd60 治疗可以改善多个器官中与年龄相关的表型。Cmpd60 减少肾脏中的肾上皮 - 间质转化和纤维化，减少大脑中与痴呆相关的基因表达，并增强心脏的心脏收缩力和松弛。总之，我们在老年小鼠中为期两周的 HDAC1/2 抑制剂治疗在哺乳动物中建立了多组织、健康的衰老干预，有望将治疗转化为促进人类健康衰老。

更新日期：2023-12-12

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