Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome

• DOI: 10.1101/2023.05.02.539084
• Publication Date: 2023-05-02T22:35:17Z
• Authors: Marisa Ferreira-M...; André Carvalho; Ana Catarina Franco; Ana Leal; Mariana Botelho; Sara Carmo-Silva; Rodolfo Águas; Luísa Cortes; Vasco Lucas; Ana Carolina Real; Carlos López-Otín; Xavier Nissan; Luís Pereira de A...; Cláudia Cavadas; Célia A. Aveleira
• Keywords: [SDV] Life Sciences [q-bio]; autophagy; senescence; human aging; [SDV]Life Sciences [q-bio]; ghrelin; 610; progeria; Research Articles; 3. Good health

AbstractHutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition arising from a single nucleotide alteration in theLMNAgene, which leads to the production of a defective lamin A protein known as progerin. The buildup of progerin hastens the onset of premature and expedited aging. Patients with HGPS exhibit short stature, low body weight, lipodystrophy, metabolic dysfunction, and skin and musculoskeletal abnormalities and, in most cases, die of cardiovascular disease by their early teenage years. Currently, no effective cure or treatment for the disease highlights the importance of discovering new therapeutic strategies. Herein, we present evidence that the hormone ghrelin, besides promoting autophagy and progerin clearance, rescued several cellular hallmarks of premature aging of human HGPS fibroblasts. Using an HGPS mouse model,LmnaG609G/G609Gmice, we also show that ghrelin administration rescued the short-lived mice molecular and histopathological progeroid features, prevented progressive weight loss at later stages, reverted the lipodystrophic phenotype, and extended lifespan. Thus, we disclose that modulation of ghrelin signaling may give rise to new treatment targets and translational approaches that may improve outcomes and the health quality of HGPS patients and natural aging pathologies.