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.
Highlights
Aging is characterized by decline in cellular function and is associated with obesity, inflammation, altered energy metabolism, and insulin resistance [1, 2]
Consistent with previous findings that young hNAG-1mice (20 to 30 weeks) are resistant to obesity on a 12 week-long HFD [14], both mean body and abdominal white adipose tissue (WAT) weights are significantly reduced in old hNAG-1 mice (> 95 weeks) after prolonged feeding with either diets (Figure 1c and 1d, Supplementary Figures 1 and 2)
Aging is characterized by decline in cellular function and is associated with obesity, inflammation, energy metabolism, and insulin resistance [1, 2]
Summary
Aging is characterized by decline in cellular function and is associated with obesity, inflammation, altered energy metabolism, and insulin resistance [1, 2]. Understanding the mechanisms of aging with the goal of increased lifespan remains an area of intensive study. Metabolic dysfunction is a common hallmark of aging [2]. The insulin/IGF-1 (IIS) signaling pathway is the most characterized metabolic pathway implicated in aging [2, 3]. Genetic suppression of IIS signaling extends longevity in worms, insects, and mammals [1]. Caloric restriction is the only efficient treatment known to increase mammalian lifespan other than genetic modifications [4]. Rodents fed a caloric restriction diet have lower IGF-1 levels than rodents fed a normal chow diet, and many rodent genetic models with a prolonged lifespan have lower levels of serum IGF-1 or IIS signaling compared to control groups [57]. HFD promotes mortality and decreases lifespan in laboratory animals [8, 9]
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