RESUMO
Green tea catechins are associated with a delay in aging. We have designed the current study to investigate the impact and to unveil the target of the most abundant green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG). Experiments were performed in Caenorhabditis elegans to analyze cellular metabolism, ROS homeostasis, stress resistance, physical exercise capacity, health- and lifespan, and the underlying signaling pathways. Besides, we examined the impact of EGCG and ECG in isolated murine mitochondria. A concentration of 2.5 µM EGCG and ECG enhanced health- and lifespan as well as stress resistance in C. elegans. Catechins hampered mitochondrial respiration in C. elegans after 6-12 h and the activity of complex I in isolated rodent mitochondria. The impaired mitochondrial respiration was accompanied by a transient drop in ATP production and a temporary increase in ROS levels in C. elegans. After 24 h, mitochondrial respiration and ATP levels got restored, and ROS levels even dropped below control conditions. The lifespan increases induced by EGCG and ECG were dependent on AAK-2/AMPK and SIR-2.1/SIRT1, as well as on PMK-1/p38 MAPK, SKN-1/NRF2, and DAF-16/FOXO. Long-term effects included significantly diminished fat content and enhanced SOD and CAT activities, required for the positive impact of catechins on lifespan. In summary, complex I inhibition by EGCG and ECG induced a transient drop in cellular ATP levels and a temporary ROS burst, resulting in SKN-1 and DAF-16 activation. Through adaptative responses, catechins reduced fat content, enhanced ROS defense, and improved healthspan in the long term.
Assuntos
Catequina/análogos & derivados , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Longevidade/efeitos dos fármacos , Chá/química , Animais , Caenorhabditis elegans , Catequina/química , Catequina/farmacologia , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Fisiológico/efeitos dos fármacosRESUMO
D-Glucosamine (GlcN) is a freely available and commonly used dietary supplement potentially promoting cartilage health in humans, which also acts as an inhibitor of glycolysis. Here we show that GlcN, independent of the hexosamine pathway, extends Caenorhabditis elegans life span by impairing glucose metabolism that activates AMP-activated protein kinase (AMPK/AAK-2) and increases mitochondrial biogenesis. Consistent with the concept of mitohormesis, GlcN promotes increased formation of mitochondrial reactive oxygen species (ROS) culminating in increased expression of the nematodal amino acid-transporter 1 (aat-1) gene. Ameliorating mitochondrial ROS formation or impairment of aat-1-expression abolishes GlcN-mediated life span extension in an NRF2/SKN-1-dependent fashion. Unlike other calorie restriction mimetics, such as 2-deoxyglucose, GlcN extends life span of ageing C57BL/6 mice, which show an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet.
Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Glucosamina/farmacologia , Longevidade/efeitos dos fármacos , Animais , Feminino , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Compounds that delay aging in model organisms may be of significant interest to anti-aging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. We here aimed to test whether pharmaceutical concentrations of L-theanine, a putative anti-cancer, anti-obesity, blood pressure-lowering, and neuroprotective compound contained in green tea (Camellia sinensis), are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. METHODS: Adult C. elegans roundworms were maintained on agar plates, were fed E. coli strain OP50 bacteria, and L-theanine was applied to agar to test (1) whether it may increase survival upon paraquat exposure and (2) whether it may promote longevity by quantifying survival in the presence and absence of the compound. RESULTS: L-Theanine increases survival of C. elegans in the presence of paraquat at a concentration of 1 micromolar. L-theanine extends C. elegans lifespan when applied at concentrations of 100 nM, as well as 1 and 10 micromolar. CONCLUSIONS: In the model organism C. elegans, L-theanine is capable of promoting paraquat resistance and longevity suggesting that this compound may as well promote healthy lifespan in mammals and possibly humans.
Assuntos
Antioxidantes/farmacocinética , Caenorhabditis elegans/efeitos dos fármacos , Glutamatos/farmacologia , Longevidade , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/administração & dosagem , Caenorhabditis elegans/crescimento & desenvolvimento , Camellia sinensis/química , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Glutamatos/administração & dosagem , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Fármacos Neuroprotetores/administração & dosagem , Concentração Osmolar , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Folhas de Planta/química , Análise de SobrevidaRESUMO
Elevated visceral adipose tissue-derived serpin (vaspin) serum concentrations are associated with impaired insulin sensitivity, but increase unexpectedly after long-term physical training. We therefore investigated the effect of an acute exercise bout and the effects of vitamin supplementation on chronic exercise effect and on serum vaspin concentrations. We measured serum vaspin and thiobarbituric acid-reactive substances (TBARS) concentrations in 80 individuals before and after a 1-hour acute exercise bout and independently in 40 healthy young men who were randomly assigned to either antioxidant (vitamin C (1,000 mg/day) and vitamin E (400 IU/day)) or to no supplementation after a standardized 4-week physical training program as a post hoc analysis. Serum vaspin concentrations significantly decreased after acute physical exercise as well as after 4 weeks of training in individuals without antioxidants. Changes in vaspin serum concentration correlate with increased TBARS serum concentrations both in response to a 1-hour exercise bout (r = -0.42, p < 0.01) and to the 4-week training (r = -0.31, p < 0.05). Interestingly, supplementation with antioxidants rather increased circulating vaspin levels in response to 4 weeks of exercise. In conclusion, vaspin serum concentrations are decreased by exercise-induced oxidative stress, but not by exercise-associated improvement in insulin sensitivity.
Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Exercício Físico/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Serpinas/sangue , Vitaminas/uso terapêutico , Adulto , Ácido Ascórbico/uso terapêutico , Biomarcadores/sangue , Glicemia/metabolismo , Regulação para Baixo , Feminino , Alemanha , Humanos , Insulina/sangue , Masculino , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de Tempo , Resultado do Tratamento , Vitamina E/uso terapêutico , Adulto JovemRESUMO
Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARgamma), and PPARgamma coactivators PGC1alpha and PGC1beta only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
Assuntos
Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Exercício Físico/fisiologia , Saúde , Adulto , Ácido Ascórbico/efeitos adversos , Ácido Ascórbico/farmacologia , Biomarcadores/sangue , Humanos , Insulina/sangue , Insulina/fisiologia , Resistência à Insulina/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Especificidade por Substrato , Fatores de Tempo , Vitamina E/efeitos adversos , Vitamina E/farmacologiaRESUMO
Increasing cellular glucose uptake is a fundamental concept in treatment of type 2 diabetes, whereas nutritive calorie restriction increases life expectancy. We show here that increased glucose availability decreases Caenorhabditis elegans life span, while impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration. The histone deacetylase Sir2.1 is found here to be dispensable for this phenotype, whereas disruption of aak-2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of life span due to impaired glycolysis. Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates, altogether providing direct evidence for a hitherto hypothetical concept named mitochondrial hormesis or "mitohormesis." Accordingly, treatment of nematodes with different antioxidants and vitamins prevents extension of life span. In summary, these data indicate that glucose restriction promotes mitochondrial metabolism, causing increased ROS formation and cumulating in hormetic extension of life span, questioning current treatments of type 2 diabetes as well as the widespread use of antioxidant supplements.