HDAC1/2 inhibitor therapy improves multiple organ systems 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.