RESUMEN
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.
RESUMEN
The advancement of medical technology has led not only to an increase in life expectancy but also to a rise in aging-related diseases. Aging promotes metabolic disorders, in turn affecting cardiovascular health. Derailment of biological processes in the pancreas, liver, adipose tissue, and skeletal muscle impairs glucose and lipid metabolism, and mitochondrial function, triggering the development of diabetes and lipid-related disorders that inflict damage on cardiac and vascular tissues. Long noncoding RNAs (lncRNAs) regulate a wide range of biological process and are one of the key factors controlling metabolism and mitochondria. Here, we discuss the versatile function of lncRNAs involved in the metabolic regulation of glucose and lipid, and mitochondrial function, and how the dysregulation of lncRNAs induces the development of various metabolic disorders and their cardiovascular consequences.