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Glycation-lowering compounds inhibit ghrelin signaling to reduce food intake, lower insulin resistance, and extend lifespan.

ABSTRACT: Non-enzymatic reactions in glycolysis lead to the accumulation of methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity and aging-associated pathologies. A combination of nicotinamide, lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low), was identified to lower glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Administration of Gly-Low reduced food consumption, lowered body weight, improved insulin sensitivity, and increased survival in both leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Unlike caloric restriction, Gly-Low modulated hypothalamic signaling by upregulating mTOR pathway signaling to inhibit ghrelin-mediated hunger response. Gly-Low also slowed hypothalamic aging and increased survival when administered as a late-life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary caloric restriction and reducing glycation.

ORGANISM(S): Mus musculus

PROVIDER: GSE234483 | GEO | 2025/02/28

REPOSITORIES: GEO

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Proteomic Analysis of Methylglyoxal Modifications Reveals Susceptibility of Glycolytic Enzymes to Dicarbonyl Stress

Project description:Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modi-fications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts.

2022-05-20 | PXD032812 | Pride

Glycation modulates glutamatergic signaling and exacerbates ParkinsonÃ¢â‚¬â„¢s disease-like phenotypes

Project description:Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for ParkinsonÃ¢â‚¬â„¢s disease (PD) and, interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction might be a contributing factor in synucleinopathies. Here, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular (ICV) injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. Notably, the glycated proteins in the midbrain of Thy1-aSyn mice that received MGO strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.

2022-05-20 | PXD032832 | Pride

caloric restriction

Project description:caloric restriction

| PRJNA87197 | ENA

IDA-SWATH proteomic analysis of rat hippocampus upon methylglyoxal treatment

Project description:Diabetes is one of the major risk factors for Alzheimer’s disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in diabetes in the pathogenesis of the AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioural study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis which may affect neurotransmission and neuronal plasticity. Hippocampal tau phosphorylation level was increased in MGO treated rats which was reduced in presence in aminoguanidine and telmisartan. Plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.

2024-01-26 | PXD037673 | Pride

Project description:Daphnia Caloric Restriction

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Project description:Zebrafish caloric restriction

| PRJNA695140 | ENA

Paternally-induced transgenerational environmental reprogramming of metabolic gene expression in mammals (Affymetrix)

Project description:Epigenetic information can be inherited through the mammalian germline, and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Characterising the change in RNA expression in sperm in response to different paternal diets. Examination of the effect of different diets, control diet, low-protein diet and caloric-restriction diet, on the RNA expression in the sperm. 8 samples: 3 are control diets and 2 are low protein diets 1 caloric restriction diet, and 2 samples from Epidydimal tissue.

2011-01-14 | E-GEOD-25896 | biostudies-arrayexpress

In vitro caloric restriction induces protective genes and functional rejuvenation in senescent SAMP8 astrocytes

Project description:Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related path- ways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mito- chondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. Key words: astrocytes; caloric restriction; mitochondria; oxidative stress; RNA microarrays; SAMP8.

2015-06-23 | GSE60388 | GEO

Impact of aging/caloric restriction on circadian gene expression

Project description:Transcriptome analysis using the liver from young versus old mice, fed either normally or under caloric restriction reveals reorganization of distinct circadian signatures related to metabolic aging and nutrient-dependent counterbalance of aging by caloric restriction

2017-07-21 | GSE93903 | GEO

Nuclear Magnetic Resonance-Based Blood Metabolic Profiles of Rats Exposed to Short-Term Caloric Restriction

Project description:Caloric restriction increases life-span of a number of organisms. The relationship between the increase in life-span and the extent of caloric restriction, however, varies among species. The underlying mechanisms are yet unknown, but appear to be related to changes in metabolism. In order to investigate the metabolic response of caloric restriction of rats, here is presented the first nuclear magnetic resonance (NMR) spectroscopy-based study of how blood metabolite profiles are influenced by graded levels of caloric restriction. The study involved three groups of obese rats exposed to 0, 20, and 40% caloric restriction for five days. Blood serum from each individual was analyzed by 1H NMR and the resulting spectra were subjected to multivariate analysis by unsupervised principal component analysis and supervised orthogonal-partial least square discriminant analysis. The analyzes revealed that a response to caloric restriction was present at 20% caloric restriction. The metabolites that distinguished the profiles at 20% restriction deviated from those at 40% restriction. The changes induced by caloric restriction were most clearly observed as an increased level of 3-hydroxybutyrate, and decreased levels of lipids and pyruvate. The metabolic responses of rats exposed to caloric restriction are in good agreement with a switch in metabolism from anabolic pathways towards fatty acid catabolism and gluconeogenesis, which is consistent with previous observations for mice.

2014-09-05 | MTBLS114 | MetaboLights

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