MDT-15/MED15 permits longevity at low temperature via enhancing lipidostasis and proteostasis

by Dongyeop Lee, Seon Woo A. An, Yoonji Jung, Yasuyo Yamaoka, Youngjae Ryu, Grace Ying Shyen Goh, Arshia Beigi, Jae-Seong Yang, Gyoo Yeol Jung, Dengke K. Ma, Chang Man Ha, Stefan Taubert, Youngsook Lee, Seung-Jae V. Lee

Low temperatures delay aging and promote longevity in many organisms. However, the metabolic and homeostatic aspects of low-temperature–induced longevity remain poorly understood. Here, we show that lipid homeostasis regulated by Caenorhabditis elegans Mediator 15 (MDT-15 or MED15), a transcriptional coregulator, is essential for low-temperature–induced longevity and proteostasis. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase that converts saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), at low temperatures. We then demonstrate that maintaining a high UFA/SFA ratio is essential for proteostasis at low temperatures. We show that dietary supplementation with a monounsaturated fatty acid, oleic acid (OA), substantially mitigates the short life span and proteotoxicity in mdt-15(-) animals at low temperatures. Thus, lipidostasis regulated by MDT-15 appears to be a limiting factor for proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of lipid regulation in maintaining normal organismal physiology under different environmental conditions.