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Scientists discover a new lead for mechanism of action of diabetes drug metformin

«Canadian and British researchers have discovered how the frontline Type 2 diabetes drug metformin may work to help cells better take up and use glucose. Their study, published today in the prestigious journal Cell, may also explain other potential beneficial effects of metformin for prevention of a variety of chronic diseases, including cancer.»

Витамины и продолжительность жизни — Остановить старение человека

«Пожизненное употребление некоторых витаминов помогает предупредить рак, болезни сердца и увеличить продолжительность жизни человека»

Changes of Cell Biochemical States Are Revealed in Protein Homomeric Complex Dynamics

«metformin appeared to make the cells act as if they are starved for the essential mineral iron»

«Our observations suggest that metformin interferes with the distribution of iron in the cell. Iron supplementation partially compensates for this perturbation. Indeed, iron metabolism is intrinsically linked to changes in central glucose metabolism, the etiological
cause of diabetes. Glycolysis itself most likely started as a Fe(II)-catalyzed network of sugar phosphate interconversions in early evolution, and a unifying function of mitochondria in all eukaryotes is the assembly of FeS clusters, a process intrinsically linked to iron transport, whereas the tricarboxylic acid (TCA) cycle and electron transport also use the FeS clusters in its catalysis (Keller et al., 2014; Lill et al., 2014)»

« We found that metformin did not reduce the intracellular iron content during exponential growth (Figure S2C) and even increased intracellular iron levels in stationary phase cultures (Figure S2D). However, the global iron deficiency-like response seems to originate from a redistribution of iron inside the cell. The level of protein-bound iron is reduced upon metformin treatment (Figure 5F; Student’s t test, p < 0.05). This result indicates that interference with iron homeostasis may lie at the heart of how metformin influences a whole spectrum of cellular processes.»

2008 Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers—a randomized, crossover intervention study

«Design and methods: A randomized controlled crossover intervention study measuring tHcy (total homocysteine) and serum folate and vitamin B12 concentration was conducted in 78 male subjects (21–70 years). Following a 2-week washout period during which no alcohol was consumed, all subjects consumed 24 g alcohol (either 240 ml red wine or 80 ml vodka)/day for a 2-week period. Following a further 2-week washout, participants consumed the alternate intervention for 2 weeks.

Results: A significant increase in plasma tHcy was observed after the 2-week red wine intervention (5%, P = 0.03), and a non-significant increase in tHcy with vodka intervention (3%, P = 0.09). When the two interventions were compared, the change in tHcy did not differ between the vodka and red wine interventions (P = 0.57). There were significant decreases in serum vitamin B12 and folate concentration, and this decrease did not differ between interventions. The increase in tHcy observed in both interventions did not vary by MTHFR 677C>T genotype.»

2011 Metformin-induced lactic acidosis: no one left behind

2014 Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required.

2015 New mechanisms of metformin action: Focusing on mitochondria and the gut

«The most well-known mechanism of metformin action, one of the most commonly prescribed antidiabetic drugs, is adenosine monophosphate-activated protein kinase activation; however, recent investigations have shown that adenosine monophosphate-activated protein kinase-independent pathways can explain some of metformin's beneficial metabolic effects as well as undesirable side-effects. Such novel pathways include induction of mitochondrial stress, inhibition of mitochondrial shuttles, alteration of intestinal microbiota, suppression of glucagon signaling, activation of autophagy, attenuation of inflammasome activation, induction of incretin receptors and reduction of terminal endoplasmic reticulum stress. Together, these studies have broadened our understanding of the mechanisms of antidiabetic agents as well as the pathogenic mechanism of diabetes itself. The results of such investigations might help to identify new target molecules and pathways for treatment of diabetes and metabolic syndrome, and could also have broad implications in diseases other than diabetes. Accordingly, new antidiabetic drugs with better efficacy and fewer adverse effects will likely result from these studies.»

2017 The mechanisms of action of metformin

«Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.»

2018 Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice

We report here that metformin can almost completely abolish glucose intolerance in female HET3 mice treated with rapamycin.

2003 Novel inhibitors of advanced glycation endproducts.

«A number of natural or synthetic compounds as AGE inhibitors have been proposed, discovered or currently being advanced by others and us. We have identified two new classes of aromatic compounds; aryl- (and heterocyclic) ureido and aryl (and heterocyclic) carboxamido phenoxyisobutyric acids, and benzoic acid derivatives and related compounds, as potential inhibitors of glycation and AGE formation. Some of these novel compounds also showed "AGE-breaking" activities in vitro. Current evidence is that chelation of transition metals and/or trapping or indirect inhibition of formation of reactive carbonyl compounds are involved in the mechanisms of action of these novel AGE inhibitors and breakers. Here, we review the inhibitors of glycation and AGE-breakers published to date and present the results of our in vitro and in vivo investigations on a number of these novel AGE inhibitors. These AGE-inhibitors and AGE-breakers may find therapeutic use in the treatment of diseases that AGE formation and accumulation may be responsible for their pathogenesis such as diabetes, Alzheimer's, rheumatoid arthritis, and atherosclerosis.»

2004 Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine.

"The contents of glucose, glycated protein, glycosylated haemoglobin and fructosamine were significantly lowered by taurine treatment to high fructose rats. Taurine prevented in vitro glycation and the accumulation of AGEs. Furthermore, taurine enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin."

2005 Taurine prevents collagen abnormalities in high fructose-fed rats.

«Fructose administration caused accumulation of collagen in tail tendon. Enhanced glycation and advanced glycation end products (AGE)-linked fluorescence together with alterations in aldehyde content, solubility pattern, susceptibility to denaturing agents and shrinkage temperature were observed in fructose-fed rats. Elevated b component of type I collagen was evidenced from the SDS gel pattern of collagen from the fructose-fed rats. Simultaneous administration of taurine alleviated these changes.»

2008 Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells.

"Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE, or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27(Kip1), collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells."

2009 Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients.

«To evaluate the efficacy of supplementation with high dose folic acid with and without vitamin B 12 in lowering plasma total homocysteine (tHcy) concentration in hemodialysis (HD) patients, we studied 36 HD patients randomized into four groups according to the received therapeutic regimen: group I (only folic acid (FA), 5 mg/day), group II (FA, 5 mg/day + vitamin B 12 , 1 mg/day) group III (only FA, 15 mg/day), group IV (FA, 15 mg/day, vitamin B 12 , 1 mg/day) for a period of 8 weeks. Plasma tHcy and serum FA and vitamin B 12 levels were measured at baseline and after the supplementation period. Dietary intakes were assessed during the study period. At baseline, 27.8% of the patients had normal levels of tHcy and 72.2% had hyperhomocysteinemia. After supplementation, plasma tHcy increased by 1.35% in group I and decreased by 6.99%, 14.54% and 30.09% in groups II, III and IV respectively, which was only significant in group IV (P= 0.014). The patients did not show any significant changes in serum folic acid, but a significant change in serum vitamin B 12 in group IV (P= 0.006). Percentage of patients reaching normal levels of plasma tHcy was 5.6 fold higher in group IV than in the reference group (group I). No correlations were found between changes of plasma tHcy levels and dietary intakes. We conclude that oral supplementation with 15 mg/day folic acid together with 1 mg/day of vitamin B 12 is effective in reducing tHcy levels in HD patients. These supplements also have a desirable effect on serum folic acid and vitamin B12.»

2010 Anabolic processes in human skeletal muscle: restoring the identities of growth hormone and testosterone.

«Testosterone supplementation acts via numerous mechanisms as a highly potent anabolic agent to skeletal muscle. Although growth hormone (GH) strongly affects collagen synthesis and lipolysis, as well as increasing lean body mass, it is not anabolic toward the contractile (ie, myofibrillar) muscle tissue in healthy individuals. However, there is a persistent belief (both in scientific literature and among recreational weightlifters) that exercise-induced release of GH and testosterone underpins muscular hypertrophy with resistance training. This is a premature assumption because although pharmacological GH supplementation can increase muscle strength or size in individuals with clinical GH deficiency, there is no evidence that transient exercise-induced changes in GH have the same effects in individuals with normal GH levels. Exercise paradigms are designed based on the assumption (not necessarily evidenced-based mechanisms) that GH and testosterone facilitate anabolic processes that lead to skeletal muscle protein accretion and hypertrophy. Our recent work disputes this assumption. Instead, our data indicate that exercise-induced hormonal elevations do not enhance intracellular markers of anabolic signaling or the acute postexercise elevation of myofibrillar protein synthesis. Furthermore, data from our training study demonstrate that exercise-induced increases in GH and testosterone availability are not necessary for and do not enhance strength and hypertrophy adaptations. Instead, our data lead us to conclude that local mechanisms that are intrinsic to the skeletal muscle tissue performing the resistive contractions (ie, weightlifting) are predominant in stimulating anabolism. The purpose of this article is 1) to provide a brief overview of the mechanisms of action of testosterone and GH; 2) to discuss the inability of physiological exercise-induced elevations in these hormone to have a measurable impact on skeletal muscle anabolism; and 3) to describe factors that we believe are more important for stimulating hypertrophy in human skeletal muscle. Clarifying both the role of hormone in regulating muscle mass as well as the underlying basis for adaptation of skeletal muscle to resistance exercise will hopefully enhance and support the prescription of resistance exercise as an integral component of a healthy lifestyle.»

2012 Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study.

A total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%.

2018 Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.

Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis.

Here we show that clinically relevant concentration of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin’s antihyperglycemic effect.

Additionally, in mice expressing constitutively active acetylCoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentration, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentration, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression.

2018 Association of metformin administration with gut microbiome dysbiosis in healthy volunteers.

"There was a significant reduction of inner diversity of gut microbiota observed already 24 hours after metformin administration. We observed an association between the severity of gastrointestinal side effects and the increase in relative abundance of common gut opportunistic pathogen Escherichia-Shigella spp. One week long treatment with metformin was associated with a significant decrease in the families Peptostreptococcaceae and Clostridiaceae_1 and four genera within these families."

2018 Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.

«Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO₂ max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.»

2019 Associations between metformin use and vitamin B12 level, anemia and neuropathy in patients with diabetes: a meta-analysis.

«31 studies were included in the meta-analyses. Compared to diabetic patients not taking metformin, patients taking metformin had significantly higher risk of B12 deficiency (RR=2.09; 95% CI [1.49, 2.93]; P<0.0001; I² =64%) and significantly lower serum B12 concentration (MD=-63.70; 95% CI [-74.35, -53.05] pmol/l; P<0.00001; I² =87%) in a duration and dose dependent manner. Metformin use was also associated with significantly greater % decrease in serum B12 concentration from baseline in diabetic patients (MD=-14.68; 95% CI [-17.98, -11.39]%; P<0.00001; I² =33%). Analyses revealed no significant association between metformin use and prevalence of anemia or neuropathy.

Metformin use led to significantly lowered B12 level and significantly higher risk of B12 deficiency in diabetic patients. More quality studies are needed to explore the associations between metformin use and anemia and neuropathy in these patients. Annual B12 assessment in diabetic patients taking metformin was recommended.»