Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti-adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine- and cysteine-titrated diets, we demonstrate that the anti-adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. In mice, the magnitude of SAAR-induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age-at-onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. Controlled feeding of low-SAA, high-polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.

• Klíčová slova
• aging, caloric restriction, cysteine, metabolic syndrome, methionine, nutrition, sulfur amino acids, triglycerides,
• MeSH
• aminokyseliny sírové * metabolismus   MeSH
• cystein * metabolismus   MeSH
• lidé MeSH
• metabolismus lipidů MeSH
• methionin metabolismus   MeSH
• myši MeSH
• obezita metabolismus   MeSH
• průřezové studie MeSH
• serin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminokyseliny sírové * MeSH
• cystein * MeSH
• methionin MeSH
• serin MeSH

Several epidemiological studies have suggested that obesity complicated with insulin resistance and type 2 diabetes exerts deleterious effects on the skeleton. While obesity coexists with estrogen deficiency in postmenopausal women, their combined effects on the skeleton are poorly studied. Thus, we investigated the impact of high-fat diet (HFD) on bone and metabolism of ovariectomized (OVX) female mice (C57BL/6J). OVX or sham operated mice were fed either HFD (60%fat) or normal diet (10%fat) for 12 weeks. HFD-OVX group exhibited pronounced increase in body weight (~86% in HFD and ~122% in HFD-OVX, p < 0.0005) and impaired glucose tolerance. Bone microCT-scanning revealed a pronounced decrease in trabecular bone volume/total volume (BV/TV) (-15.6 ± 0.48% in HFD and -37.5 ± 0.235% in HFD-OVX, p < 0.005) and expansion of bone marrow adipose tissue (BMAT; +60.7 ± 9.9% in HFD vs. +79.5 ± 5.86% in HFD-OVX, p < 0.005). Mechanistically, HFD-OVX treatment led to upregulation of genes markers of senescence, bone resorption, adipogenesis, inflammation, downregulation of gene markers of bone formation and bone development. Similarly, HFD-OVX treatment resulted in significant changes in bone tissue levels of purine/pyrimidine and Glutamate metabolisms, known to play a regulatory role in bone metabolism. Obesity and estrogen deficiency exert combined deleterious effects on bone resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass. Our results suggest that obesity may increase bone fragility in postmenopausal women.

• Klíčová slova
• Aging, bone fragility, accelerated aging, bone marrow adiposity, menopause, obesity, osteoporosis, senescence,
• MeSH
• diabetes mellitus 2. typu * komplikace   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• estrogeny MeSH
• kosti a kostní tkáň metabolismus   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita komplikace   metabolismus   MeSH
• ovarektomie škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• estrogeny MeSH

A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.

• Klíčová slova
• cardiac, ischemia-reperfusion, remodeling, senescence, senolytic,
• MeSH
• lidé MeSH
• reperfuzní poškození metabolismus   MeSH
• stárnutí buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Increasing maternal age in mammals is associated with poorer oocyte quality, involving higher aneuploidy rates and decreased developmental competence. Prior to resumption of meiosis, fully developed mammalian oocytes become transcriptionally silent until the onset of zygotic genome activation. Therefore, meiotic progression and early embryogenesis are driven largely by translational utilization of previously synthesized mRNAs. We report that genome-wide translatome profiling reveals considerable numbers of transcripts that are differentially translated in oocytes obtained from aged compared to young females. Additionally, we show that a number of aberrantly translated mRNAs in oocytes from aged females are associated with cell cycle. Indeed, we demonstrate that four specific maternal age-related transcripts (Sgk1, Castor1, Aire and Eg5) with differential translation rates encode factors that are associated with the newly forming meiotic spindle. Moreover, we report substantial defects in chromosome alignment and cytokinesis in the oocytes of young females, in which candidate CASTOR1 and SGK1 protein levels or activity are experimentally altered. Our findings indicate that improper translation of specific proteins at the onset of meiosis contributes to increased chromosome segregation problems associated with female ageing.

• MeSH
• lidé MeSH
• oocyty metabolismus   MeSH
• savci MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low-density lipoprotein receptor-deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft-bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

• Klíčová slova
• aging, cancer, chemoinformatics, computational screening, metformin,
• MeSH
• biokatalýza MeSH
• experimentální nádory farmakoterapie   metabolismus   MeSH
• histondemethylasy antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• jaderné proteiny antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• metformin chemie   farmakologie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• myši MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondemethylasy MeSH
• inhibitory enzymů MeSH
• jaderné proteiny MeSH
• KDM6A protein, human MeSH Prohlížeč
• ligandy MeSH
• metformin MeSH
• Utx protein, mouse MeSH Prohlížeč

In response to DNA damage, a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after DNA damage until terminal cell cycle exit. This low level of Cdk activity not only allows cell cycle progression, but also promotes cell cycle exit at a decision point in G2 phase. We find that residual Cdk1/2 activity is required for efficient p21 production, allowing for nuclear sequestration of Cyclin B1, subsequent APC/CCdh1 -dependent degradation of mitotic inducers and induction of senescence. We suggest that the same activity that triggers mitosis in an unperturbed cell cycle enforces senescence in the presence of DNA damage, ensuring a robust response when most needed.

• Klíčová slova
• Cdk1, Cdk2, DNA damage response, G2 phase, cell cycle, checkpoint recovery, p21, senescence,
• MeSH
• analýza jednotlivých buněk MeSH
• buněčné linie MeSH
• CD antigeny MeSH
• chinoliny farmakologie   MeSH
• cyklin B1 genetika   metabolismus   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• epitelové buňky cytologie   účinky léků   enzymologie   MeSH
• etoposid farmakologie   MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• kadheriny genetika   metabolismus   MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• osteoblasty cytologie   účinky léků   enzymologie   MeSH
• poškození DNA MeSH
• proteinkinasa CDC2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• pteridiny farmakologie   MeSH
• puriny farmakologie   MeSH
• regulace genové exprese MeSH
• retinální pigmentový epitel cytologie   účinky léků   enzymologie   MeSH
• signální transdukce MeSH
• stárnutí buněk účinky léků   MeSH
• thiazoly farmakologie   MeSH
• velikost buňky MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 4-(6-cyclohexylmethoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide MeSH Prohlížeč
• BI 2536 MeSH Prohlížeč
• CCNB1 protein, human MeSH Prohlížeč
• CD antigeny MeSH
• CDH1 protein, human MeSH Prohlížeč
• CDK1 protein, human MeSH Prohlížeč
• CDK2 protein, human MeSH Prohlížeč
• chinoliny MeSH
• cyklin B1 MeSH
• cyklin-dependentní kinasa 2 MeSH
• etoposid MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• kadheriny MeSH
• proteinkinasa CDC2 MeSH
• pteridiny MeSH
• puriny MeSH
• RO 3306 MeSH Prohlížeč
• thiazoly MeSH

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood-brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic.

• Klíčová slova
• Alzheimer's disease, Aβ, Tg2576, advanced glycation end product, blood-brain barrier, receptor for advanced glycation end product,
• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• dieta MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• náhodné rozdělení MeSH
• produkty pokročilé glykace aplikace a dávkování   metabolismus   MeSH
• prostorové učení fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• produkty pokročilé glykace MeSH

Cells with overactive RAS/protein kinase A (PKA) signaling, such as RAS2(Val19) cells, exhibit reduced proliferation rates and accelerated replicative senescence. We show here that the extended generation time of RAS2(Val19)cells is the result of abrogated ATP/ADP carrier activity of the mitochondria. Both PKA-dependent and independent routes are responsible for inhibiting ATP/ADP exchange in the RAS-overactive cells. The reduced carrier activity is due, at least in part, to elevated levels of reactive oxygen species (ROS), which also cause a proteolysis-dependent fragmentation of the Aac2p carrier both in vivo and on isolated mitochondria. Attenuated carrier activity is suppressed by overproducing the superoxide dismutase, Sod1p, and this enhances both the proliferation rate and the replicative longevity of RAS2(Val19) cells. In contrast, overproducing functional Aac2p restored proliferation but not longevity of RAS2(Val19) cells. Thus, Ras signaling affects proliferation rate and replicative lifespan by two different, ROS-dependent, routes. While the reduction in generation time is linked to the inactivation, specifically, of the mitochondrial nucleotide carrier, longevity is affected by other, and hitherto unknown, target(s) of ROS attack.

• MeSH
• aktivace enzymů MeSH
• down regulace MeSH
• genetické inženýrství MeSH
• mitochondriální ADP/ATP-translokasy biosyntéza   nedostatek   metabolismus   MeSH
• mutantní proteiny MeSH
• proliferace buněk MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• Ras proteiny genetika   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny biosyntéza   MeSH
• Saccharomyces cerevisiae enzymologie   genetika   růst a vývoj   MeSH
• signální transdukce MeSH
• stárnutí buněk MeSH
• superoxiddismutasa biosyntéza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální ADP/ATP-translokasy MeSH
• mutantní proteiny MeSH
• PET9 protein, S cerevisiae MeSH Prohlížeč
• proteinkinasy závislé na cyklickém AMP MeSH
• Ras proteiny MeSH
• reaktivní formy kyslíku MeSH
• Saccharomyces cerevisiae - proteiny MeSH
• superoxiddismutasa MeSH