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.

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'.