A Novel HDAC1/2 Inhibitor Improves Measures of Tissue Function in Aged Mice – Fight Aging!

A Novel HDAC1/2 Inhibitor Improves Measures of Tissue Function in Aged Mice

Researchers here report on the results of a drug screen focused on mimicking the transcriptional changes that occur in a number of interventions shown to modestly slow aging in short-lived species. They find an inhibitor of histone deacetylases HDAC1 and HDAC2 achieves this outcome, and note that in mice this drug candidate can produce positive changes in a number of measures of tissue function. Further studies will have to explore longer-term effects, dosing, and side-effects. Histone decacetylases influence the structure of the nuclear genome, and thus also influence gene expression quite broadly. Understanding how and why benefits result from this drug candidate will be a long-term undertaking. Further one should probably expect a sizable chance of undesirable side-effects, given what is known of this class of small molecule drug. Other histone deacetylases are under development for treatment of a range of conditions. Inhibition of HDAC1 seems positive here, but other research has shown that upregulation is beneficial in the context of aging neurons.

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.

Link: https://doi.org/10.1016/j.isci.2023.108681

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