Related Experiment Video
Updated: Jul 5, 2025
Short Session High Intensity Interval Training and Treadmill Assessment in Aged Mice
Published on: February 2, 2019
HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice
Alessandra Tammaro1, Eileen G Daniels2,3, Iman M Hu2,3
1Amsterdam UMC location University of Amsterdam, Department of Pathology, Amsterdam Infection & Immunity, Amsterdam, the Netherlands.
Abstract:
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.
Insights
A new drug, compound 60 (Cmpd60), a histone deacetylase 1 and 2 (HDAC1/2) inhibitor, shows promise for healthy aging. This compound improved age-related conditions in multiple organs in aged mice.
Area of Science:
- Gerontology
- Pharmacology
- Molecular Biology
Background:
- Aging is a primary risk factor for numerous chronic diseases, leading to significant health burdens.
- Pharmacological targeting of aging mechanisms offers a strategy to enhance healthspan and mitigate disease risk.
Purpose of the Study:
- To identify compounds that mimic the transcriptional profiles of genetic longevity interventions.
- To evaluate the therapeutic potential of a novel compound for promoting healthy aging.
Main Methods:
- Transcriptome-based drug screening was utilized to discover candidate compounds.
- Compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, was identified and characterized.
- Extensive molecular, phenotypic, and bioinformatic analyses were performed in cellular and aged mouse models.
Main Results:
- Cmpd60 effectively mimicked transcriptional signatures associated with longevity interventions.
- Treatment with Cmpd60 improved age-related phenotypes across multiple organs in aged mice.
- Specific improvements included reduced kidney fibrosis, diminished dementia-related gene expression in the brain, and enhanced cardiac function.
Conclusions:
- Selective HDAC1/2 inhibition by Cmpd60 represents a promising multi-tissue intervention for healthy aging in mammals.
- A short-term (two-week) treatment regimen demonstrated significant benefits, suggesting therapeutic potential for human application.
