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Research Paper|Volume 6, Issue 8|pp 690—704

hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling

Xingya Wang1,4, Kali Chrysovergis1, Justin Kosak1, Grace Kissling2, Mike Streicker3, Glenda Moser3, Ruifang Li1, Thomas E. Eling1
  • 1Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709; USA
  • 2Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709; USA
  • 3Integrated Laboratory Systems, Inc., Morrisville, NC 27560, USA
  • 4College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Zhejiang, China 310053
Received: June 23, 2014Accepted: August 24, 2014Published: August 28, 2014
https://doi.org/10.18632/aging.100687

Copyright: © 2014 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) or GDF15 is a divergent member of the transforming growth factor beta (TGF-β) superfamily and mice expressing hNAG-1/hGDF15 have been shown to be resistant to HFD-induced obesity and inflammation. This study investigated if hNAG-1 increases lifespan in mice and its potential mechanisms. Here we report that female hNAG-1 mice had significantly increased both mean and median life spans in two transgenic lines, with a larger difference in life spans in mice on a HFD than on low fat diet. hNAG-1 mice displayed significantly reduced body and adipose tissue weight, lowered serum IGF-1, insulin and glucose levels, improved insulin sensitivity, and increased oxygen utilization, oxidative metabolism and energy expenditure. Gene expression analysis revealed significant differences in conserved gene pathways that are important regulators of longevity, including IGF-1, p70S6K, and PI3K/Akt signaling cascades. Phosphorylation of major components of IGF-1/mTOR signaling pathway was significantly lower in hNAG-1mice. Collectively, hNAG-1 is an important regulator of mammalian longevity and may act as a survival factor. Our study suggests that hNAG-1 has potential therapeutic uses in obesity-related diseases where life span is frequently shorter.