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.
A very interesting compound, dosing information and result… I think this is an area we will see increasing activity going forward.
To determine Cmpd60’s geroprotective effects on the kidney at the molecular and physiological levels, we proceeded to treat aged male mice (20 months old) via intraperitoneal injection for 14 days with either Cmpd60 (22.5mg/kg) or control (Figure 2B).
This is the compound tested:
Cmpd60, also known as Merck60. Broad Institute ID number BRD6929 and CAS No.: 849234-64-6
BRD6929 is a histone deacetylase 1 (HDAC1) and HDAC2 inhibitor (IC50s = 0.04 and 0.1 µM, respectively, for the recombinant human enzymes).1 It is selective for HDAC1 and HDAC2 over HDAC3 and HDAC8 (IC50s = >20 µM for both).
It is clearly stronger than things like Curcurmin and Pterostilbene which are in the 20-50 micro Molar range.
However, personally I am inclined to go for the natural substances that people have eaten a lot of over the years. That results in weaker inhibition, but some probability that the side effects are either benign or known.
In the end we don’t want to inhibit HDAC too much.
My hypothesis is that HDAC inhibition slows down the deacetylation process so that a stalled RNA Pol II is not turfed off the histone/gene and into an alternative/aberrant splice as often.
Incidentally I have been giving the interplay between DNA methylation and acetylation some thought and I wonder if methylation occurs gradually, but is removed by gene transcription. Hence inactive genes get methylated which discourages transcription, but this can be reversed by a transcription happening.
This looks very promising. It seems like there should be several teams working on it. ITP should put it in, but the pricing is outrageous, unless the dosage is very very small.
And from John’s description of HDAC, it seems like you need it to happen.
In regards to the interplay, I agree that methylation occurs gradually vs acetylation(since acetylation is typically dynamic and involved in quick gene expression processes such as IEGs or memory/neuron activity), although I wonder how it would work in regards to the heritablity of methylation. Also I believe there is more evidece coming out that DNA methylation may be more dynamic that once thought, although not sure how it would compare to acetylation.
Another thing I think about is that Methylation can directly interfere with the binding of DNA and transcription factors, or it can attract proteins that bind specifically to modify DNA, thereby blocking other transcription factors from binding the site. I do know about methyl-CpG-binding domain (MBD) and nucleosome remodeling deacetylase (NuRD) protein constitute the chromatin remodeling complex and bind to methylated CpG, which later turns off the transcription of the gene. MeCP2 represses gene expression by introducing histone deacetylase (HDAC) 1 and 2 and Sin3A to the gene, removing acetyl groups from acetylated histone tails. it clear that there is an association between DNA methylation and histone deacetylation via a methylated DNA binding protein, MeCP2. The induction of histone deacetylation by MeCP2 was found to have a connection with Sin3A, which interacts with HDAC. It has been demonstrated that MeCP2 consists of the MBD and transcriptional repression domain (TRD), and that TRD interacts with Sin3A, which brings HDAC to the histone of methylated DNA. In human lymphoma cell lines treated with phorbol myristate acetate and butyrate(HDAC inhibitor), levels of methylated CpG were decreased. This finding means that inhibition of histone deacetylation induced demethylation of DNA.
Similarly, when HEK 293 cells were treated with trichostatin A (TSA), which inhibits histone deacetylation, genes were demethylated actively in a replication-independent manner… I wonder how much other epigenetic modifications also occur during these processes and contribute to what we see with gene activity (an example may be polycomb complexes) vs just the contribution of inhibitng HDAC or methylation.
I am very excited to see where the literature goes in regards to HDAC inhibitors and other inhibitors of the histone acetylation pathway as there have been lots of evidence indicating their therapeutic value in cognition and other disease states such as neurodegeneration.
