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

Wang, Xingya; Chrysovergis, Kaliopi; Kosak, Justin; Kissling, Grace E.; Streicker, Mike; Moser, Glenda J.; Li, Ruifang; Eling, Thomas E.

doi:10.18632/aging.100687

Cited by 92 publications

(67 citation statements)

References 36 publications

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“…DUSP10 preferentially dephosphorylates p38 MAPK [49]. Growth differentiation factor 15 ( GDF15 ) was the top upregulated AMPK-independent gene (Fig 2B) and its overexpression is known to result in improved insulin sensitivity [50]. The transporter solute carrier family 19, member 3 ( SLC19A3 ) was also an upregulated AMPK-dependent gene (S1 Table), and is known to play a role in the intestinal absorption and tissue distribution of metformin [51].…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Metformin Hepatic Response

et al. 2016

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Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.

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Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Metformin Hepatic Response

et al. 2016

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“…Several recent reports have shown the association of GDF15 with aging and longevity. Female transgenic mice overexpressing human GDF15 in various tissues, such as skin, colon, kidney, brain and adipose tissues, present a prolongation of both mean and median lifespans, and the effects are more prominent in mice fed a high‐fat diet than in those fed a low‐fat diet . In contrast, several epidemiological studies have shown an association between GDF15 and all‐cause mortality.…”

Section: Agingmentioning

confidence: 99%

Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders

Fujita

Taniguchi

Shinkai

et al. 2016

Geriatrics Gerontology Int

147

119

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We and other have recently shown that growth differentiation factor 15 (GDF15) is a useful diagnostic marker for mitochondrial diseases, which are inherited disorders caused by mitochondrial or nuclear genomic mutations that lead to impaired energy production. As the primary cause of mitochondrial diseases is mitochondrial dysfunction, the blood level of GDF15 might reflect mitochondrial function in patients, and thus could be a marker for mitochondrial dysfunction. GDF15 has been implicated in aging and various age-related disorders, such as cardiovascular diseases and diabetes, the blood level of which is reportedly elevated in older adults as well as in patients. Although GDF15 might be induced as a result of various cellular stresses and dysfunctions, it would also be possible that the blood GDF15 level reflects at least in part mitochondrial dysfunction in aging and age-related disorders. In the present review, we summarized the current literature regarding GDF15 in aging and age-related disorders from the perspective of biomarkers, with a particular focus on mitochondrial dysfunction. Geriatr Gerontol Int 2016; 16 (Suppl. 1): 17-29.

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“…Notably, we here show that the induction of Gdf15 was not affected by the loss of FGF21 action. It was previously shown that overexpression of Gdf15 in mice prevents dietinduced obesity and increases lifespan by activating adipose tissue as well as systemic energy metabolism [66,67]. Conversely, circulating levels of GDF15 are also highly elevated in patients with muscle atrophy [68] and in cancer patients with severe anorexia and weight loss [69] and chronic inflammation [70].…”

Section: Discussionmentioning

confidence: 99%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

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Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21 À/À ) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR mt ) and amino acid biosynthetic pathways did not require the presence of FGF21.Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

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

Cited by 92 publications

References 36 publications

Genomic Characterization of Metformin Hepatic Response

Genomic Characterization of Metformin Hepatic Response

Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

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