HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice.

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.

Reducing mitochondrial ribosomal gene expression does not alter metabolic health or lifespan in mice.

Maintaining mitochondrial function is critical to an improved healthspan and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the gene expression of a critical MRP, Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygous Mrpl54 mice. Despite reduced Mrpl54 expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or female Mrpl54+/- and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no differences in glucose or insulin tolerance, treadmill endurance, cold tolerance, heart rate, or blood pressure. There were no differences in median life expectancy or maximum lifespan. Overall, we demonstrate that genetic manipulation of Mrpl54 expression reduces mitochondrial-encoded protein content but is not sufficient to improve healthspan in otherwise healthy and unstressed mice.

Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.

Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.

From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs.

Reversing or slowing the aging process brings great promise to treat or prevent age-related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the "classical" histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age-related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition.

A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder.

Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited from one parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial-encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells to DNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.

Re-exposure and environmental enrichment reveal NPY-Y1 as a possible target for post-traumatic stress disorder.

Exposure-based cognitive behavioral therapy in post-traumatic stress disorder (PTSD) patients relieves symptoms caused by fear association as well as symptoms that are not the result of associative learning. We used the inescapable foot shock model (IFS), an animal model for PTSD, to study the possible involvement of glutamate receptors, the corticotropin-releasing factor (CRF) system, and the neuropeptide Y (NPY) system in the reduction of stress sensitization following repeated re-exposure to the conditioning context. Starting one week after the IFS procedure, the rats were repeatedly re-exposed to the shock environment. Stress sensitivity was measured in a modified open field test (sudden silence was used as a stressor). Selected mRNAs (GluN1, -2A-C, GluA1-4, GluK1-5, CRF, CRF-R1, NPY, NPY-Y1) were quantified in the amygdala. Repeated re-exposure (RE) to the IFS context reduced both trauma-associated anxiety (to the IFS context) and the enhanced stress sensitivity (in the open field). Changes in glutamate receptor subunits (GluN1, GluN2A-B, GluA1, GluA4, GluK3, GluK4) were detected in the amygdala that were normalized by RE. However, infusion of the AMPA/kainate antagonist NBQX in the BLA (basolateral amygdala) did not improve the anxious behavior. RE normalized IFS-induced increases in CRF-R1 mRNA and increased NPY-Y1 mRNA expression in the amygdala. Previously, and repeated here, we showed that environmental enrichment (EE) enhances recovery from IFS. EE led to similar changes in CRF-R1 and NPY-Y1 expression as RE did. Importantly, administration of [Leu31, Pro34]-NPY (Y1 agonist) in the BLA normalized the enhanced sensitivity to stress after IFS. Our data suggest that the NPY-Y1 receptor in the amygdala may serve as a therapeutic target for the treatment of PTSD.