Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice

Aging Cell

Jong Hee Park³  Hae Young Chung²  Minkyu Kim¹  Jung Hwa Lee³  Mankil Jung¹ 

[1] Department of Chemistry, Yonsei University, Seoul, Korea;Aging Tissue Bank, Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Korea;Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Global Top 5 Research Program, Seoul, Korea

关键词: aging;    inflammation;    insulin resistance;    liver;    longevity;    pheromones;   

DOI  :  10.1111/acel.12224

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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