title: hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling.
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.
authors.affiliation: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709, USA. College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Zhejiang, China 310053.
authors.forename: Xingya
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Chrysovergis
authors.affiliation: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Kosak
authors.affiliation: Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Kissling
authors.affiliation: Integrated Laboratory Systems, Inc., Morrisville, NC 27560, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Streicker
authors.affiliation: Integrated Laboratory Systems, Inc., Morrisville, NC 27560, USA.
authors.forename: Glenda
authors.initials: G
authors.lastname: Moser
authors.affiliation: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709, USA.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park NC 27709, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D058570:TOR Serine-Threonine Kinases