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


A related Q&A with the Bimini: A Retrieval Augmented Generation (RAG) AI (OpenAI 4 Turbo) with 22 years of FightAging articles to retrieve to augment its generation:

A recent study of an inhibitor of histone deacetylases HDAC1 and HDAC2 (Cmpd60) reduced dementia-related gene expression in brain. What are the most harmful dementia-related gene expression in brain, and can you suggest other chemicals that might reduce these?

Run instructions
You are an expert in the science of the delay and prevention of human aging and cellular senescence. You are focused around the prevention and repair of cellular damage. You are able to retrieve and synthesize information with the goal of driving forward the field of negligible senescence. You will prefer newer information over older.

Dementia is characterized by the loss of cognitive functioning-thinking, remembering, learning, and reasoning-and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Various mechanisms at the genetic level contribute to the development and progression of dementia, including Alzheimer's disease, which is the most common form of dementia.

The most harmful dementia-related gene expressions in the brain involve genes that are associated with the pathological hallmarks of dementia, such as the buildup of amyloid-beta plaques and tau tangles, neuroinflammation, oxidative stress, and the loss of synaptic function. Key genes implicated in dementia include:

Amyloid precursor protein (APP): Mutations in the APP gene can lead to the overproduction of toxic amyloid-beta peptides, which aggregate to form plaques.
Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2): Mutations in these genes affect the processing of APP, leading to an increase in the production of toxic amyloid-beta 42, a particularly aggregative form.
Apolipoprotein E (APOE) ε4 allele: The presence of this allele is a strong risk factor for late-onset Alzheimer's disease, likely through mechanisms involving amyloid-beta deposition and clearance.
Microtubule-associated protein tau (MAPT): Abnormal phosphorylation of tau proteins causes them to aggregate into neurofibrillary tangles, which are a hallmark of various types of dementia.
Triggering receptor expressed on myeloid cells 2 (TREM2): Variants in this gene are associated with an increased risk of Alzheimer's disease, potentially through mechanisms involving immune responses and phagocytosis in the brain.
To address the detrimental gene expressions mentioned, compounds that target these pathways may be beneficial. In addition to Cmpd60 (an inhibitor of histone deacetylases HDAC1 and HDAC2), other chemicals and compounds that might reduce harmful dementia-related gene expressions include:

Beta-secretase (BACE) inhibitors: These drugs inhibit BACE1, an enzyme involved in the production of amyloid-beta, thus potentially reducing amyloid plaque formation.

Gamma-secretase modulators: These compounds selectively modulate the cleavage of APP by gamma-secretase, reducing the production of the toxic amyloid-beta 42 peptide.

Anti-tau therapies: Methods to reduce tau pathology include tau aggregation inhibitors, anti-tau antibodies for immunotherapy, and inhibitors of tau phosphorylation.

Antioxidants: Compounds such as Vitamin E, resveratrol, and curcumin are thought to mitigate oxidative stress, which contributes to the pathogenesis of dementia.

Immunomodulatory drugs: Targeting neuroinflammation through such drugs can be beneficial, with minocycline and the use of monoclonal antibodies against pro-inflammatory cytokines being some examples.

Sirtuin activators: Compounds such as resveratrol also act as sirtuin activators. Sirtuins (particularly SIRT1) have been suggested to have neuroprotective effects in the context of dementia and Alzheimer's disease.

A comprehensive strategy integrating these therapeutic approaches, considering the multifactorial nature of dementia, would likely be the most effective path forward in the management and treatment of this condition. It's also worth noting that ongoing research might uncover novel targets and compounds with potential efficacy against dementia-related gene expressions.

Posted by: Tom Schaefer at February 7th, 2024 9:30 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.