title: Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice.
abstract: The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics. Daumone [(2)-(6R)-(3,5-dihydroxy-6-methyltetrahydropyran-2-yloxy)heptanoic acid], a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction. Daumone (2 mg kg(-1) day(-1) ) was administered orally for 5 months to 24-month-old male C57BL/6J mice. Daumone was found to reduce the risk of death by 48% compared with age-matched control mice, and the increased plasma insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated β-galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. From a mechanistic view, daumone reduced the phosphorylation of the IκBα and upregulation of Rela and Nfkbia mRNA in the livers of old mice. The anti-inflammatory effect of daumone was confirmed in lipopolysaccharide-induced liver injury model. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound.
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Global Top 5 Research Program, 52 Ewhayoedae-gil, Seodaemun-gu, Seoul, Korea.
authors.forename: Jong Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Minkyu
authors.initials: M
authors.lastname: Kim
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Lee
authors.forename: Mankil
authors.initials: M
authors.lastname: Jung
authors.forename: Hunjoo
authors.initials: H
authors.lastname: Ha
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D005227:Fatty Acids / Q000008:administration & dosage / Q000494:pharmacology*; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D005247:Feeding Behavior / Q000187:drug effects*; D018149:Glucose Intolerance / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010675:Pheromones / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016019:Survival Analysis; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007328:Insulin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010675:Pheromones; C496586:daumone, C elegans; D001616:beta-Galactosidase
keywords: aging; inflammation; insulin resistance; liver; longevity; pheromones