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Oral Glycotoxins Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan
Abstract
We previously showed that the content of advanced glycation end products (AGEs) in the diet correlates with serum AGE levels, oxidant stress (OS), organ dysfunction, and lifespan. We now show that the addition of a chemically defined AGE (methyl-glyoxal-BSA) to low-AGE mouse chow increased serum levels of AGEs and OS, demonstrating that dietary AGEs are oxidants that can induce systemic OS. OS predisposes to the development of cardiovascular and chronic kidney diseases; calorie restriction (CR) is the most studied means to decrease OS, increase longevity, and reduce OS-related organ damage in mammals. Because reduction of food intake also decreases oxidant AGE s intake, we asked whether the beneficial effects of CR in mammals are related to the restriction of oxidants or energy. Pair-fed mice were provided either a CR diet or a high-AGE CR diet in which AGEs were elevated by brief heat treatment (CR-high). Old CR-high mice developed high levels of 8-isoprostanes, AGEs, RAGE, and p66(shc), coupled with low AGER1 and GSH/GSSG levels, insulin resistance, marked myocardial and renal fibrosis, and shortened lifespan. In contrast, old CR mice had low OS, p66(shc), RAGE, and AGE levels, but high AGER1 levels, coupled with longer lifespan. Therefore, the beneficial effects of a CR diet may be partly related to reduced oxidant intake, a principal determinant of oxidant status in aging mice, rather than decreased energy intake.
... A exemplo de medidas de CML (carboximetillisina), pelo método de ELISA (ensaio de imunoabsorbância ligado à enzima), usando anticorpos monoclonais específicos para cada tipo de amostra dificulta sua utilização no Brasil por haver disponível apenas Kit para análise em sangue. Os métodos por HPLC (cromatografia líquida de alta eficiência) e por GC-MS (cromatografia gasosa-espectrometria de massa) baseados em mensurações de BSA (albumina sérica bovina) modificada pela glicose, CML-BSA sintética e MG-BSA [16] precisam de tratamentos específicos para a extração das amostras. Outro método para mensurar AGEs é a fluorescência, mas a natureza da fluorescência pode ser muito heterogênea e não relacionada aos produtos de glicação [11]. ...
... Os AGEs realizam ligações cruzadas intra e intermoleculares, formando estruturas estáveis com proteínas estruturais e com proteínas intracelulares, afetando principalmente proteínas de meia-vida biológica longa. No entanto, compostos de meia-vida curta também são glicados, como a lipoproteína de baixa densidade (LDL), facilitando a oxidação de proteínas e lipídios, a perda da conformação molecular, a alteração das funções proteicas, resultando em não reconhecimento pelos receptores e clearance anormal [4,10,14,15,16,21]. Há dois grandes mecanismos de ação dos AGEs, um deles depende da ativação de RAGE, o que determina a disfunção celular e endotelial [14]. ...
... O turnover de AGEs é regulado em parte por receptores, que participam da degradação de proteínas modificadas pela glicação, provocando sua excreção renal. Entretanto, esses receptores são ineficientes em condições de estresse oxidativo [4,16,19,21]. ...
Objetivo: Esta revisão objetiva investigar a contribuição dos Produtos de Glicação Avançada (AGEs) dietéticos na aterosclerose para a otimização da dietoterapia. Metodologia: O presente estudo realizou um levantamento bibliográfico sobre estudos publicados nos bancos de dados Medline, PUBMed, Periódicos CAPES, ScienceDirect e SciELO no período de 1997 a 2015. Síntese dos dados: Os AGEs dietéticos são absorvidos e se juntam aos AGEs endógenos, exercendo atividades pró-oxidantes e pró-inflamatórias, concorrendo para a inflamação, o estresse oxidativo e a lesão vascular, através do aumento da glicação de proteínas e da interação AGE-receptor. A glicação de lipoproteínas, ligações cruzadas entre AGEs e proteínas da parede dos vasos e o aumento da vasoconstrição estimulam o desenvolvimento da aterosclerose. Conclusão: A glicação de proteínas e seus produtos atuam claramente no desenvolvimento da aterosclerose. A ingestão dos AGEs dietéticos deve ser reduzida na abordagem terapêutica da aterosclerose. Alimentos submetidos a técnicas culinárias como ferver, cozinhar e ensopar devem ser preferencialmente ingeridos. Alimentos fontes de lipídeos e proteínas processados a altas temperaturas são fontes de AGEs e devem ser evitados. Juntas, essas estratégias contribuem para a redução do pool de AGEs no organismo.Palavras-chave: produtos finais de glicosilação, dieta, aterosclerose, doenças cardiovasculares.
... Recent animal and human studies with an oral intake of an AGE-rich meal, labelled AGEs or specific AGEs have clearly demonstrated that dietary AGEs represent an important source for circulating AGEs and contribute to the in vivo AGEs pool under physiological conditions [17,[20][21][22][23][24]. ...
... In healthy individuals, there are associations between serum AGEs levels and the risk factors for developing chronic diseases. Generally, the circulating AGEs levels are positively correlated with age, oxidative stress and insulin resistance [21,25,33]. Higher levels of AGEs have been found in healthy individuals with high dietary AGEs intakes than in individuals who eat foods containing fewer AGEs [91]. ...
... This is generally related to the effects of AGEs on protein dysfunction, oxidative stress and inflammation. Dietary AGEs have been shown to be correlated with serum levels of AGEs, inflammation markers, metabolic dysfunction and life expectancy [5,21,24,25], suggesting that dietary AGEs are pathogenic, and predisposing the body to the development of CVD, diabetes and other chronic diseases, possibly via inducing systemic oxidative stress [21]. Animal studies demonstrated that AGEs supplementation promotes oxidative stress [21,45,106]. ...
Abstract Advanced glycation end products (AGEs), a group of compounds that are formed by non-enzymatic reactions between carbonyl groups of reducing sugars and free amino groups of proteins, lipids or nucleic acids, can be obtained exogenously from diet or formed endogenously within the body. AGEs accumulate intracellularly and extracellularly in all tissues and body fluids and can cross-link with other proteins and thus affect their normal functions. Furthermore, AGEs can interact with specific cell surface receptors and hence alter cell intracellular signaling, gene expression, the production of reactive oxygen species and the activation of several inflammatory pathways. High levels of AGEs in diet as well as in tissues and the circulation are pathogenic to a wide range of diseases. With respect to mobility, AGEs accumulate in bones, joints and skeletal muscles, playing important roles in the development of osteoporosis, osteoarthritis, and sarcopenia with aging. This report covered the related pathological mechanisms and the potential pharmaceutical and dietary intervention strategies in reducing systemic AGEs. More prospective studies are needed to determine whether elevated serum AGEs and/or skin autofluorescence predict a decline in measures of mobility. In addition, human intervention studies are required to investigate the beneficial effects of exogenous AGEs inhibitors on mobility outcomes.
... Animal and human data indicate that RAGE expression is likely modulated by environmental factors, including AGEs [119,120] and disease states such as diabetes [98,101]. Whilst increased levels of full length, membrane-bound RAGE are associated with disease progression and poor outcomes in both animal models and humans [100,101,104], circulating soluble forms are inversely correlated with metabolic parameters, including body mass index (BMI), serum triglycerides, HbA1c, insulin resistance [121], and chronic disease [122][123][124][125][126][127], and positively associate with longevity [128,129]. ...
... The effects of dietary AGEs on insulin sensitivity is vitally important, since abnormalities in glucose homeostasis are potent risk factors for CKD development and progression. In animal models, increasing circulating AGEs [174,175] and consumption of diets high in AGEs [160,162,167,176] irrefutably result in decreased insulin sensitivity, independent of other dietary factors [119,160]. In humans, several studies have demonstrated a relationship between high AGE diets and insulin signalling defects [177] with acute changes in insulin secretion following high AGE meal challenges [178,179]. ...
Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a "western" diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, individuals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.
... The data from animal studies were further confirmed by clinical studies [1][2][3][4][5]12] using diets with different amounts of AGEs according to a large database of different foods, which were subjected to standard cooking methods (boiling, broiling, deep-frying, oven-frying, and roasting) [13,14]. and normal diet (g 13.5 kcal% fat, 24 kcal% protein, and 62.5 kcal% carbohydrates) High fat fed rats showed increased body weight, free fatty acids, glucose, insulin, HOMA-IR index, enzymatic antioxidant activity, total antioxidant/oxidant status and oxidative damage products (TAC, TOS, OSI, and FRAP), activity of NOX and XO) in the cerebral cortex and hypothalamus, and enzymatic antioxidants (GPx, CAT, and SOD-1) in the cerebral cortex Qu et al. 2017 [27] Sprague-Dawley rats L-AGEs diet or high-AGEs diet H-AGEs fed rats showed markedly decreased diversity of cecal microbiota, after 18 weeks of feeding, increased proportion of proteobacteria, and decreased proportion of Bacteroidetes; in the short-term feeding period of 6 weeks, significantly higher relative abundance of five genera, including Prevotella, Oscillibacter, Phascolarctobacterium, Akkermansia, and Gastranaerophilales; higher concentration of ammonia in cecal contents and significantly lower concentration of two other genera, Lachnospiraceae and Mucispirillum at 12 and 18 weeks of feeding; decreased acetate and propionate from 6 to 18 weeks; and modestly increased butyric acid and histological score of colonic tissue High fat fed mice showed increased adiposity and premature insulin resistance; severe deficiency of AGER1 and SIRT1 in white adipose tissue, skeletal muscle, and liver; impaired 2-deoxy-glucose uptake; marked changes in insulin receptor IRS-1, IRS-2; Akt activation; and a macrophage and adipocyte shift to a pro-oxidant/inflammatory phenotype Cai et al. 2008 [36] C57BL/6 mice Caloric restriction (40% reduction in calories), caloric restriction exposed to heating, the same CR diet, in which the content of (by 15 min at 120 • C, and standard formula) ...
... In another study, Cai et al. showed that pair-fed mice on a calorie-restricted H-AGEs diet developed high levels of 8-isoprostanes, AGEs, AGER-1, and p66shc, coupled with low AGER-1 and glutathione/oxidized glutathione ratio, IR, marked myocardial and renal fibrosis, and shortened lifespan, compared with those on a calorie-restricted diet alone. This study showed that H-AGEs intake competed against the benefits of calorie-restriction and that healthspan seems to be increased by calorie-restriction in terms of consumption of foods containing L-AGEs [36]. ...
The increased incidence of obesity, diabetes mellitus, aging, and associated comorbidities indicates the interplay between genetic and environmental influences. Several dietary components have been identified to play a role in the pathogenesis of the so-called “modern diseases”, and their complications including advanced glycation end products (AGEs), which are generated during the food preparation and processing. Diet-derived advanced glycation end products (dAGEs) can be absorbed in the gastrointestinal system and contribute to the total body AGEs’ homeostasis, partially excreted in the urine, while a significant amount accumulates to various tissues. Various in vitro, in vivo, and clinical studies support that dAGEs play an important role in health and disease, in a similar way to those endogenously formed. Animal studies using wild type, as well as experimental, animal models have shown that dAGEs contribute significantly to the pathogenesis of various diseases and their complications, and are involved in the changes related to the aging process. In addition, they support that dAGEs’ restriction reduces insulin resistance, oxidative stress, and inflammation; restores immune alterations; and prevents or delays the progression of aging, obesity, diabetes mellitus, and their complications. These data can be extrapolated in humans and strongly support that dAGEs’ restriction should be considered as an alternative therapeutic intervention.
... Dietary AGEs (dAGEs) are similar in structure, and function almost identically, to endogenous AGEs, and are therefore important contributors to the body's AGE pool. [6] During food preparation, nutrients such as carbohydrate, protein, and fat could interact and react to form AGEs. [7] Many studies have reported that restriction of dAGEs prevents vascular and kidney dysfunction, [8,9] diabetes (type 1 or type 2), [10] improves insulin sensitivity [1,11] and also reduces markers of oxidative stress and inflammation in healthy and overweight individuals. [12] Many western studies have been conducted with the representative AGE compound N e -carboxymethyl lysine (CML), a low molecular weight AGE that might be absorbed from the gut and contribute to the endogenous pool of AGEs in the body. ...
... [12] Many western studies have been conducted with the representative AGE compound N e -carboxymethyl lysine (CML), a low molecular weight AGE that might be absorbed from the gut and contribute to the endogenous pool of AGEs in the body. [6] Asian Indian cuisine varies considerably by region. There are various cooking methods used in the preparation of Indian foods, which include steaming, boiling, frying (deep-frying, and shallow frying), and baking, many of which could result in amplified levels of AGEs. ...
... While a life-long calorie restriction (of about 40% calories/day) significantly prolonged the life-span in mice, survival of animals consuming similarly calorie-restricted but AGEs-rich diet tended to be shorter compared with that of mice consuming a regular diet (Cai et al., 2008). In comparison with a standard diet, consumption of calorie-restricted AGEs-rich diet imposed about 70% higher daily dCML load. ...
... Earlier manifestation of neurological reflexes might indicate accelerated brain maturation. As a life-long consumption of AGEs-rich diet associates with shorter life-span in rodents (Peppa et al., 2003;Cai et al., 2008), question arises whether accelerated brain maturation is a forerunner of accelerated ageing. ...
Advanced glycation end products (AGEs) are formed in in vivo, and accumulate in tissues and body fluids during ageing. Endogenous AGE-modified proteins show altered structure and function, and may interact with receptor for AGEs (RAGE) resulting in production of reactive oxygen species, inflammatory, atherogenic and diabetogenic responses. AGEs are also formed in thermally processed foods. Studies in rodents document that dietary AGEs are partially absorbed into circulation, and accumulate in different tissues. Knowledge on the health effects of high dietary intake of AGEs is incomplete and contradictory. In this overview we discuss the data from experimental and clinical studies, either those supporting the assumption that restriction of dietary AGEs associated with health benefits, or data suggesting that dietary intake of AGEs associates with positive health outcomes. We polemicize whether the effects of exaggerated intake or restriction of highly thermally processed foods might be straightforward interpreted as the effects of AGEs-rich vs. AGEs-restricted diets. We also underline the lack of studies, and thus a poor knowledge, on the effects of different single chemically defined AGEs administration, concurrent intake of different dietary AGEs, of load with dietary AGEs corresponding to the habitual diet in humans, and on those of dietary AGEs in vulnerable populations, such as infants and particularly elderly.
... The modern human diet and most pelleted experimental animal food contain a ubiquitous group of environmental factors, including glycation endproducts (AGEs), which are strong inducers of OS/Infl and are a risk factor for DKD and chronic kidney disease (CKD) [7,8,10,11,16,17]. We found that GS develops as OS/Infl increases in normal aging, and that GS can be reduced by controlling the oral intake of agents that increase OS/Infl, such as AGEs [18]. ...
... This pilot study has several limitations including the relatively short follow-up period, the absence of a treated non-DB control or male mice, the presence of tissue and OS/Infl marker studies only at study end, and the small size of the study groups. Since the relatively large amount of oxidant AGEs in the usual animal chow, was not modified in this study [17,18], a more pronounced effect of dietary oxidants on OS/Infl might have been seen if their restriction, by either low AGE food or drugs that bind AGEs in food had been utilized [55, 56]. These pilot data suggest that additional drugs that might preserve OS/Infl defenses should be explored. ...
Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic. Since GS also develops in aged C57Bl6 mice, and can be reversed using bone marrow from young mice which have lower oxidative stress and inflammation (OS/Infl), we postulated that this might also apply to DKD. Therefore, this pilot study asked whether reducing OS/Infl in young adult sclerosis-prone (ROP) diabetic mice leads to resolution of existing GS in early DKD using safe, FDA-approved drugs.After 4 weeks of stable streptozotocin-induced hyperglycemia 8–12 week-old female mice were randomized and treated for 22 weeks as follows: 1) enalapril (EN) (n = 8); 2) pyridoxamine (PYR)+EN (n = 8); 3) pentosan polysulfate (PPS)+EN (n = 7) and 4) PPS+PYR+EN (n = 7). Controls were untreated (non-DB, n = 7) and hyperglycemic (DB, n = 8) littermates. PPS+PYR+EN reduced albuminuria and reversed GS in DB. Treatment effects: 1) Anti-OS/Infl defenses: a) PPS+PYR+EN increased the levels of SIRT1, Nrf2, estrogen receptor α (ERα) and advanced glycation endproduct-receptor1 (AGER1) levels; and b) PYR+EN increased ERα and AGER1 levels. 2) Pro-OS/Infl factors: a) PPS+PYR+EN reduced sTNFR1, b) all except EN reduced MCP1, c) RAGE was reduced by all treatments. In summary, PYR+PPS+EN modulated GS in sclerosis-prone hyperglycemic mice. PYR+PPS+EN also decreased albuminuria, OS/Infl and the sclerosis-prone phenotype. Thus, reducing OS/Infl may reverse GS in early diabetes in patients, and albuminuria may allow early detection of the sclerosis-prone phenotype.
... A life-long restriction of AGE containing diet reduces oxidative stress generation and AGE accumulation which are associated with RAGE and p66 suppression, resulting in extension of lifespan in mice [71]. Oral intake of AGE-containing foods also determines the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan [148]. These observations suggest that restriction of AGE-rich diet may be a novel therapeutic target for prevention of age associated various disorders. ...
... In humans dietary glycotoxins significantly increase concentrations of systemic inflammatory mediators like TNFα, interleukin (IL)-6 and C-reactive protein and are thus considered as diabetogenic, nephrotoxic and proatherogenic [92,214]. Dietary intake of AGEs correlates with serum AGEs and can induce systemic oxidative stress, increase RAGE expression, decrease antioxidant levels and shorten lifespan in mice [148]. A diet with a low content in AGEs could reduce circulating AGEs and inflammatory biomarkers in patients with Diabetes and renal failure thus seeming to be an important supportive therapy in Diabetes [215,216]. ...
First described in the context of diabetes, advanced glycation end products (AGEs) are formed through a type of non-enzymatic reaction called glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis, and, recently, skin aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. Characteristic findings of aging skin, including decreased resistance to mechanical stress, impaired wound healing, and distorted dermal vasculature, can be in part attributable to glycation. Multiple factors mediate cutaneous senescence, and these factors are generally characterized as endogenous (e.g., telomere shortening) or exogenous (e.g., ultraviolet radiation exposure). Interestingly, AGEs exert their pathophysiological effects from both endogenous and exogenous routes. The former entails the consumption of sugar in the diet, which then covalently binds an electron from a donor molecule to form an AGE. The latter process mostly refers to the formation of AGEs through cooking. Results of several studies in animal models and humans show that the restriction of dietary AGEs has positive effects on wound healing, insulin resistance and cardiovascular diseases. Recently, the effect of restriction in AGEs intake has been reported to increase the lifespan in animal models. Recent studies have revealed that certain methods of food preparation (i.e. grilling, frying, and roasting) produce much higher levels of AGEs than water-based cooking methods such as boiling and steaming. Moreover, several dietary compounds have emerged as promising candidates for the inhibition of glycation-mediated aging. In this chapter, we summarize the evidence supporting the critical role of glycation in skin aging and highlight preliminary studies on dietary strategies that may be able to combat this process.
... Detailed analysis showed that mice from the high-AGE CR group developed higher levels of 8-isoprostanes, AGEs, RAGE, and oxidative stress regulatory protein p66shc, coupled with low AGE-R1, GSH, and oxidised glutathione levels, decreased insulin resistance, marked myocardial and renal fibrosis, and a shortened lifespan. In contrast, control CR mice had lower oxidative stress markers, p66shc, RAGE and AGE levels, but high AGE-R1 levels, coupled with a longer lifespan [286]. These results support the hypothesis that oxidative stress can be reduced and the health span increased by consuming a diet where the AGE content is restricted. ...
Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.
... Binding of AGEs to receptor for AGE (RAGE) on myocytes and endothelial cells in skeletal muscle has been shown to release proinflammatory cytokines (including interleukin 6 -IL-6 and tumor necrosis factor alpha -TNFα) via activation of the transcription factor NF-kB and induce generation of reactive oxygen species [40]. Multiple human intervention studies showed an association of low AGE diet with lower levels of inflammation markers (CRP, IL-6 and TNFα) [41,42]. Chronically raised levels of inflammation markers (IL-6 and TNFα) have been demonstrated in individuals with both sarcopenia and frailty in epidemiological studies [43][44][45]. ...
Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent.
We investigated the relationship between dietary intake of carboxymethyllysine (dCML) – an AGE prototype – and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study.
Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia.
2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01–1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86–1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91–1.07)] or frailty [OR = 1.01 (0.83–1.22)] when non-frail subjects were used as reference.
Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.
... The hypothesis focused on Advanced Glycation End Products (AGEs) and trans-fatty acids (TFAs), markers of many neo-formed contaminants (NFCs), as an additional molecular mechanism behind increased hyperglycaemia and atherosclerosis among South Asians. This hypothesis was based on animal and human studies linking increased exposure to NFC's, particularly AGEs and TFA's, with certain cooking techniques [18], resulting in inflammation, insulin resistance and CKD [19]. While NFC's have been linked to CKD in animal and human studies [20e22] their relevance to South Asian populations specifically, though proposed by Bhopal [23], has not been investigated. ...
Background and aims
The occurrence of chronic heart and kidney diseases among the South Asian populations has been rising exponentially over the years. Research has been carried out in the past to explain the increased susceptibility with no resultant strong evidence. Various possible causes have been suggested with a previous hypothesis suggestive of high heat cooking techniques being responsible for increased production of neo-formed contaminants such as advanced glycation end products (AGEs) and trans-fatty acids (TFAs) leading to increased chronic heart diseases among the South Asian diaspora (India, Pakistan, Bangladesh, Sri Lanka in South Asia and overseas). The aim of this study proposes the high-heating cooking techniques and subsequent NFCs also to be responsible for the development of chronic kidney ailments among the South Asians.
Methods
Review of the literature was conducted to ascertain the burden of accumulation and actions of AGEs and TFAs on kidney structure and functions. The varied high-heat cooking techniques including reheating of oils, food processing and kinds of food sources and their association with increased NFCs production and kidney damage were explored.
Results
Higher NFCs content of AGEs/TFAs in reheated oils at elevated temperatures and TFAs among processed and fast foods of South Asians was associated with elevated diabetic complications and CKDs progression in few animal and human studies but the research on the actual burden of NFCs in the renal tissues of South Asians was lacking.
Conclusion
We hypothesize the high heat cooked foods generating increased levels of NFCs to be responsible for the preponderance of higher risk of CKDs among South Asians. Scientific exploration of the hypothesis to obtain quantifiable evidence of NFCs is suggested.
... Data from clinical trials accentuate the critical role of the high dietary intake of AGEs molecules in triggering and promoting inflammatory and oxidative reactions [110,114]. There are several approaches for reducing the dietary AGEs including, lowering the cooking temperature, decreasing cooking time, and using higher humidity and moisture during food preparation, caloric restriction is another way for diminishing exogenous AGEs [115][116][117][118]. Fats and meats tend to contain more dietary AGE per gram of weight, given that reducing butter, cream cheese, margarine, beef, and hamburger in a routine regimen can help lessen exogenous AGEs. ...
Coronavirus Disease 2019 (COVID-19), caused by the novel virus SARS-CoV-2, is often more severe in older adults. Besides age, other underlying conditions such as obesity, diabetes, high blood pressure, and malignancies, which are also associated with aging, have been considered risk factors for COVID-19 mortality. A rapidly expanding body of evidence has brought up various scenarios for these observations and hyperinflammatory reactions associated with COVID-19 pathogenesis. Advanced glycation end products (AGEs) generated upon glycation of proteins, DNA, or lipids play a crucial role in the pathogenesis of age-related diseases and all of the above-mentioned COVID-19 risk factors. Interestingly, the receptor for AGEs (RAGE) is mainly expressed by type 2 epithelial cells in the alveolar sac, which has a critical role in SARS-CoV-2-associated hyper inflammation and lung injury. Here we discuss our hypothesis that AGEs, through their interaction with RAGE amongst other molecules, modulates COVID-19 pathogenesis and related comorbidities, especially in the elderly.
... However, animal data also suggest that the positive outcome of calorie-restriction might be due to a decreased dAGE-content. Several studies show a detrimental effect of heated diets in rodents compared to the unheated equivalent in isocaloric diets [69,70]. However, as was pointed out by Buetler et al. ...
The prevalence of inflammatory bowel diseases (IBD) is increasing in the world. The introduction of the Western diet has been suggested as a potential explanation of increased prevalence. The Western diet includes highly processed food products, and often include thermal treatment. During thermal treatment, the Maillard reaction can occur, leading to the formation of dietary advanced glycation endproducts (dAGEs). In this review, different biological effects of dAGEs are discussed, including their digestion, absorption, formation, and degradation in the gastrointestinal tract, with an emphasis on their pro-inflammatory effects. In addition, potential mechanisms in the inflammatory effects of dAGEs are discussed. This review also specifically elaborates on the involvement of the effects of dAGEs in IBD and focuses on evidence regarding the involvement of dAGEs in the symptoms of IBD. Finally, knowledge gaps that still need to be filled are identified.
... In the meantime, AGE-R1 blocks oxidative damage and inflammatory responses activated by the AGE-RAGE axis, thereby enhancing the body's defense against a high AGE burden (Vlassara & Striker, 2011) (Figure 4). As with RAGE, several diet-restricted studies have evidenced a relevance between upregulated AGE-R1 and positive health outcomes related with oxidative stress, aging, insulin resistance, and atherosclerosis (Cai et al., 2007(Cai et al., , 2008(Cai et al., , 2012Lin et al., 2002;Uribarri et al., 2011;Vlassara et al., 2009). However, the binding affinities of AGE-R1 with food-derived AGEs are still unknown. ...
Dietary advanced glycation end products (dAGEs) are complex and heterogeneous compounds derived from non-enzymatic glycation reactions during industrial processing and home cooking. There is mounting evidence showing that dAGEs are closely associated with various chronic diseases, where the absorbed dAGEs fuel the biological AGEs pool to exhibit noxious effects on human health. Currently, due to the uncertain bioavailability and rapid renal clearance of dAGEs, the relationship between dAGEs and biological AGEs remains debatable. In this review, we provide the most updated information on dAGEs including their generation in processed foods, analytical and characterization techniques, metabolic fates, interaction with AGE receptors, implications on human health and reducing strategies. Available evidence demonstrating a relevance between dAGEs and food allergy is also included. AGEs are ubiquitous in foods and their contents largely depend on the reactivity of carbonyl and amino groups, along with surrounding condition mainly pH and heating procedures. Once being digested and absorbed into the circulation, two separate pathways can be involved in the deleterious effects of dAGEs: an AGE receptor-dependent way to stimulate cell signals, and an AGE receptor-independent way to dysregulate proteins via forming complexes. Inhibition of AGEs formation during food processing and reduction in the diet are two potent approaches to restrict health-hazardous dAGEs. To elucidate the biological role of dAGEs towards human health, the following significant perspectives are raised: molecular size and complexity of dAGEs; interactions between unabsorbed dAGEs and gut microbiota; and roles played by concomitant compounds in the heat-processed foods.
... Since 2002, a number of published studies in mice and rats have shown that diets high in MRPs (as specifically measured by CML) may promote many of the chronic metabolic diseases common in the United States such as diabetes and nonalcoholic fatty liver and cardiovascular diseases [52]. Diets with high CML loads have been shown to promote glucose intolerance [53][54][55], liver inflammation [54,56,57], and cardiac inflammation [58] when compared to diets lower in CML. In addition, a recent study found that a diet high in MRPs was associated with negative changes in gut health including an increase in inflammation, a reduction in fecal SCFAs, and a reduction in the diversity of the fecal microbiome [59]. ...
Animal models of chronic disease are continuously being refined and have evolved with the goal of increasing the translation of results to human populations. Examples of this progress include transgenic models and germ-free animals conventionalized with human microbiota. The gut microbiome is involved in the etiology of several chronic diseases. Therefore, consideration of the experimental conditions that may affect the gut microbiome in pre-clinical disease is very important. Of note, diet plays a large role in shaping the gut microbiome and can be a source of variation between animal models and human populations. Traditionally, nutrition researchers have focused on manipulating the macronutrient profile of experimental diets to model diseases such as metabolic syndrome. However, other dietary components found in human foods, but not in animal diets, can have sizable effects on the composition and metabolic capacity of the gut microbiome and, as a consequence, manifestation of the chronic disease being modeled. The purpose of this review is to describe how food matrix food components, including diverse fiber sources, oxidation products from cooking, and dietary fat emulsifiers shape the composition of the gut microbiome and influence gut health.
... Understanding the mechanisms through which dietary AGEs cause pathological interactions on the kidney is of key importance toward more effective goal setting in CKD treatments, which is associated with lifestyle and improvement in dietary recommendations [6]. The data that have been derived from experimental models, as well as from studies on humans, show that the increased intake of dietary AGEs promotes the progression of kidney failure. ...
Aim
The advanced glycation end products (AGEs) are among the mechanisms responsible for the
pathogenesis and development of chronic kidney disease. The aim of this study was to estimate
the dietary AGE intake and to assess its correlation with hematological and biochemical
markers of patients with end-stage renal disease (ESRD) undergoing hemodialysis.
Materials and methods
For this study, a structured questionnaire of the exogenous AGEs was developed, whose
reliability and validity were evaluated in the pilot phase of the study including 50 participants.
The questionnaire was issued to 605 participants (305 ESRD patients undergoing hemodialysis
and 300 controls), and a blood sample was obtained through which hematological and
biochemical markers were analyzed.
Results
It was noted that patients with ESRD consume large quantities of dietary AGEs not only in
absolute values but also in comparison with control subjects (p = 0.001), attributed mainly to
the methods of product processing as well as cooking. It was also ascertained that dietary AGEs
were correlated (p < 0.005) with fasting glucose and glycated hemoglobin (HbA1c) and with
lipidemic profile markers, such as triglyceride, as well as inflammation markers, such as
erythrocyte sedimentation rate, ferritin, and C-reactive protein. All the aforementioned
markers show abnormally increased levels in patients with ERSD and diabetes compared with
healthy subjects.
Conclusion
Patients with ESRD consuming foods favoring AGE formations combined with increased
endogenous AGE burden the body with their harmful action. If the specific group of patients adopt dietary habits contributing to the containment or the inhibition of AGE formation, then
this would lead to the improvement of their hematological and biochemical markers and in
terms of the effects of AGEs on their health is deemed imperative through the creation of
consulting and prevention programs.
... The incidence of obesity worldwide has paralleled the increased use of Western-style diets, which in addition to the well-established macronutrient differences (eg, higher fat content), also contain high levels of exogenous AGEs (23). Remarkably, increased dietary AGE intake results in significant elevation of circulating AGEs (28), including CEL, methylglyoxal (MGO), and CML (29), providing evidence that orally ingested AGEs are absorbed and circulated throughout the body, a process that is enhanced in foods with high fat content (30) and especially in those rich in saturated fatty acids (31). This likely results from lipoxidation providing excess substrates for AGE formation and induction of the myeloperoxidase inflammatory pathway (32), which contributes to the formation of AGEs (33), thereby creating a feed-forward-fueled pathological loop. ...
The role of advanced glycation end products (AGEs) in promoting and/or exacerbating metabolic dysregulation is being increasingly recognized. AGEs are formed when reducing sugars non-enzymatically bind to proteins or lipids, a process that is enhanced by hyperglycemic and hyperlipidemic environments characteristic of numerous metabolic disorders including obesity, diabetes and its complications. In this mini-review, we put forth the notion that AGEs span the spectrum from cause to consequence of insulin resistance (IR) and diabetes, and represent a “common soil” underlying the pathophysiology of these metabolic disorders. Collectively, the surveyed literature suggests that AGEs, both those that form endogenously as well as exogenous AGEs derived from environmental factors such as pollution, smoking and “Western” style diets, contribute to the pathogenesis of obesity and diabetes. Specifically, AGE accumulation in key metabolically-relevant organs induces IR, inflammation and oxidative stress, which in turn provide substrates for excess AGE formation, thus, creating a feed-forward fueled pathological loop mediating metabolic dysfunction.
... Sugar-derived AGEs (fructose-and glucose-derived) treatment promoted lifespan extension in wt C. elegans. This is in contrast to data from Drosophila melanogaster [25] and mice [26], where AGEs treatment accelerated aging or attenuated the beneficial effects of caloric restriction, respectively. Nevertheless, Ravichandran et al. [27] have shown that low doses of MG extend the lifespan of wt C. elegans through proteohormesis by mimicking mediators of glycine-C-acetyltransferase impairment, known to promote lifespan extension in C. elegans. ...
All living organisms are normally undergoing aging. Dietary habits constitute the main environmental factor that may accelerate or decelerate this process. Advanced glycation end products (AGEs) are constituents of dietary products that are consumed daily, such as bread and milk. Although AGEs have been widely regarded as toxic agents, recent studies seem to contradict this view: they either find no adverse effects of AGEs or even attribute beneficial properties to them. The aim of our study was to investigate the effects of sugar-derived AGEs on organismal lifespan using as a model the nematode Caenorhabditis elegans. Exposure to sugar-derived AGEs prolonged the lifespan of wild type animals; this lifespan extension was accompanied by an enhanced pharyngeal pumping rate. We demonstrate that elevation of the pharyngeal pumping rate depends on W06A7.4 and eat-4 expression, as well as on daf-16, which encodes a FOXO family transcription factor. Our results suggest that sugar-derived AGEs modulate the lifespan of C. elegans at least in part through transcriptional regulation of pharyngeal pumping throughout the animals’ lifespan.
... The heart and vasculature are not independent entities and therefore changes in the heart can affect the vasculature and vice versa [21]. Int [23] • Aging [21] • Immunosenescence [24] • ROS oxidize LDL cholesterol oxidized LDL is phagocytosed by macrophages macrophages release pro-inflammatory mediators and ROS cause further LDL oxidation atherosclerosis [25,26] • MPO promotes oxidation of LDL and limit NO availability vascular dysfunction [27] • Decreased NO leads to decline in SOD3 levels cause age-related vascular dysfunction [28] • O2 •-reacts with NO form ONOO - endothelial cell damage [26] • XO induced O2 •-formation interacts with EGFR induces vascular remodeling CVD [26] • Senescent T cells release effector molecules stimulate release of cytokines such as IFN-γ amplify inflammation [29] • IL-1β and IFN-γ induces M1 phenotype increases arterial plaques [30] • CCL-2 activates ERK1/NF-κB pathways increases atherosclerotic plaque formation [30] • SIRT1 coupled with Rel/p65 inhibits NF-κB pathway reduces systemic inflammation and impaired vessel dilation function [31] • Decrease in telomerase activity in plaques telomeric exhaustion accumulation of senescent endothelial cells VSMC proliferation vascular remodeling [24] • LTL shortening increased senescent epithelial cells pathogenic vascular remodeling [32] • SIRT1 activator [33,34] • Medicinal antiinflammatory plant [35] • Polyphenols [36] • BDB [37] • Mediterranean diet [38] • Fecal microbiota transplantation [39] Int. J. Mol ...
It has been proposed that a chronic state of inflammation correlated with aging known as inflammaging, is implicated in multiple disease states commonly observed in the elderly population. Inflammaging is associated with over-abundance of reactive oxygen species in the cell, which can lead to oxidation and damage of cellular components, increased inflammation, and activation of cell death pathways. This review focuses on inflammaging and its contribution to various age-related diseases such as cardiovascular disease, cancer, neurodegenerative diseases, chronic obstructive pulmonary disease, diabetes, and rheumatoid arthritis. Recently published mechanistic details of the roles of reactive oxygen species in inflammaging and various diseases will also be discussed. Advancements in potential treatments to ameliorate inflammaging, oxidative stress, and consequently, reduce the morbidity of multiple disease states will be explored.
... Others include, lactoylglutathione lyase and mitochondrial hydroxyacylglutathione hydrolase, two enzymes changed by a HFD which are involved in the detoxification of methylglyoxal which may be exacerbated in our model given the presence of both long-chain saturated fatty acids and refined carbohydrates in our experimental diet. Methylglyoxal is one of the most reactive glycation agents produced in vivo [26] glycating proteins, nucleotides and lipids and leading to the formation of advanced glycation end products (AGEs), which are causative in tissue damage seen in diabetes [27] and associated with AD [28]. Hippocampal neurons are particularly susceptible to methylglyoxal-induced neurotoxicity characterised by inflammation and apoptotic cell death [29,30]. ...
Background:
The rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer's disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired.
Methods:
In this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure.
Results:
HFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media.
Conclusion:
This study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure.
... 37 Some authors observed that a restriction in dietary intake of AGEs led to a reduction in oxidative stress and suppression of RAGE mRNA levels and protein concentrations in people and rats with diabetes. 38,39 Similarly, restricting intake of AGEs reduced RAGE concentrations in healthy human peripheral blood mononuclear cells and in people with diabetes to below their baseline, indicating that RAGE is regulated by AGEs in the external environment. 31,40 Oxidative stress is an inflammatory mediator. ...
Context:
Consumption of dietary advanced glycation end products (AGEs) is associated with oxidative stress, inflammation, and other chronic conditions commonly associated with obesity.
Objective:
To analyze the effects of dietary AGEs on complications associated with obesity.
Data sources:
This systematic review was conducted and reported according to PRISMA guidelines. The PubMed, Cochrane, and Scopus databases were searched, using the terms "advanced glycation end products," "overweight," and "obesity." The last search was performed in October 2018.
Data extraction:
Six studies that evaluated the effects of low-AGE and high-AGE diets were included in the review. The duration of the studies ranged from 1 day to 12 weeks. A comparison of all the compiled data was conducted by the authors.
Data analysis:
Circulating and urinary AGE markers, besides soluble receptor for AGEs, were considered as the primary outcomes. The secondary outcomes were cardiometabolic, inflammatory, glycemic, anthropometric, and renal markers.
Conclusions:
AGE-RAGE interactions can activate the NF-κB (nuclear factor kappa B) signaling pathway and inhibit the PI3K-AKT pathway in adipocytes, which may explain their association with chronic diseases. This interaction can be considered as a novel explanation for the pathogenesis of obesity. AGEs can also be used as a biomarker for monitoring responses to dietary interventions in overweight and obese people.
Systematic review registration:
PROSPERO registration no. CRD42018082745.
... However, on a positive note, restriction in dietary AGEs showed an improvement in wound healing, insulin resistance, and cardiovascular diseases [27]. It has also been shown that their restriction improved the lifespan of animal models [28]. Interactions of AGEs with the receptor for advanced glycated end-products (RAGE) and other receptors, such as AGE-R1, AGE-R2, and AGE-R3, accelerate oxidative stress by forming reactive oxygen species (ROS) [21]. ...
Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities (Kd) for GOLD and CML towards T2R4 in the nM and μM range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC50 10.52 ± 4.7 μM, whilst CML was less effective with IC50 32.62 ± 9.5 μM. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC50 of 79.35 ± 29.16 μM and 65.31 ± 17.79 μM, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.
... Moreover, an alternative to antioxidant administration is the promotion of the cellular antioxidant defense capacity to restore the redox status and prevent diabetes or aging-related damage [46]. As an example, Caloric Restriction (CR), which has a well-established antiaging action, diminishes oxidative stress and age-related diseases [47,48]. CR modulates several important inflammatory signaling pathways involved in aging and inflammation, such as mammalian Target Of Rapamycin (mTOR), Nuclear Factor (NF)-κB and Mitogen Activated Protein Kinases (MAPK) [49] and attenuates the age-related upregulation of IL-1β, IL-6, and TNFα [47]. ...
Immune systems have evolved to recognize and eliminate pathogens and damaged cells. In humans, it is estimated to recognize 10 ⁹ epitopes and natural selection ensures that clonally expanded cells replace unstimulated cells and overall immune cell numbers remain stationary. But, with age, it faces continuous repertoire restriction and concomitant accumulation of primed cells. Changes shaping the aging immune system have bitter consequences because, as inflammatory responses gain intensity and duration, tissue-damaging immunity and inflammatory disease arise. During inflammation, the glycolytic flux cannot cope with increasing ATP demands, limiting the immune response's extent. In diabetes, higher glucose availability stretches the glycolytic limit, dysregulating proteostasis and increasing T-cell expansion. Long-term hyperglycemia exerts an accumulating effect, leading to higher inflammatory cytokine levels and increased cytotoxic mediator secretion upon infection, a phenomenon known as diabetic chronic inflammation. Here we review the etiology of diabetic chronic inflammation and its consequences on wound healing.
... Studies have proposed that exogenous AGEs such as CML and MG are able to predispose individuals to an abnormal increase in oxidative stress and inflammation. CML-BSA (bovine serum albumin) and MG-BSA derived AGEs shown to promote T2D as well as T1D via early autoimmune cytotoxic T-cell activation, high-fat-fed and aging in mice models (Melpomeni et al., 2003;Sandu et al., 2005;Cai et al., 2008). ...
Mankind exposure to chemicals in the past century has increased dramatically throughout environment. There is no question that chemicals interfere with the physiology of biological system. Abundance of chemicals is documented to be detrimental to human and wildlife. The mammalian endocrine system is comprised of many interacting tissues mediate themselves through hormones that are essential for metabolism, growth and development. Humans secrete over fifty different hormones to orchestrate major physiological functions however; these vital functions can be intervened by huge number of internal and external chemical stressors that are identified as endocrine disruptors. Advanced glycation end products (AGEs), familiarly known as Maillard products, formed through non-enzymatic glycation whose production is augmented on aging as well as environmental stressors. Processed foods have become very popular today due to their taste, convenience, and inexpensiveness. Manufacture of these day-to-day foods involves extreme temperatures on processing results in the formation of AGEs could independently promote oxidative stress, aging, diabetes, cancer, degenerative diseases, more fascinatingly hormonal disruption is the subject of interest of this review. Based on some substantial observations documented till time, we discuss the emergence of dietary AGEs as potential endocrine disruptors by emphasizing their occurrence, mechanisms and participation in endocrine interruption. Both economically and in terms of human life, AGEs may represent an enormous cost for the future society. Therefore, by explicating their novel role in endocrine diseases, the review strives to make an impact on AGEs and their exposure among public as well as scientific communities.
... The research team at Mount Sinai School of Medicine, NYC, doing a large share of the research over the past 30 years regarding AGE, in two companion studies dealt a huge blow to the venerated dogma that feeding mice a food restricted diet is equivalent to caloric restriction [5,6]. Standard mouse chow is exposed to high heat for preservation. ...
... Therefore, even though especially postmitotic tissues of brain, kidney, and heart are more susceptible to age-related oxidative modifications and degenerative events, CR seems to have a considerable potential in slowing down the aforementioned ROS-induced degenerative process in these tissues. It was previously reported that increased AGE levels are associated with increased mortality and morbidity (Cai et al., 2008;Guilbaud et al., 2016). AGEs show their biological effects through receptor for AGE (mRAGE). ...
Despite recent studies have shown that caloric restriction (CR) could improve some functional loss associated with brain aging, the biochemical effects of CR on brain aging are still not well understood on a quantifiable biochemical basis, including whether CR could be protective when started around middle adulthood, when age‐related neurodegenerative diseases are thought to set in. Therefore, in the light of more than ever aging societies and increasing neurodegenerative diseases, we aimed to test the biochemical effects of CR on redox homeostasis in different parts of male Sprague‐Dawley rat brain by using the biomarkers we consistently validated in our previous work (TOS, PCO, AOPP, AGEs, sRAGE, P‐SH, LHPs, 4‐HNE, TAS, Cu, Zn‐SOD). Our results indicate that oxidative stress biomarkers are lower in CR group, implying a more favorable redox status that has been previously shown to be correlated with better neural function.
Practical applications
We report that the beneficial effects of caloric restriction (CR) on various brain tissues result in significant improvements in biochemical markers, even though CR is not started in early adulthood. Hence, our select age group provides a sound redox status‐related neurochemical understanding for many recent CR studies, where a functional loss was detected at this age.
... C57BL/ 6 mice consuming a lifelong calorie-restricted AGE-RD had a shorter life-span compared with the mice fed a standard chow diet. 96 Thus, earlier maturation of reflexes could mirror earlier maturation of the CNS, which might be in turn a forerunner of accelerated ageing. Moreover, accumulation of AGEs in the CNS has been demonstrated in different neurodegenerative diseases. ...
Maternal exposure to a Western type diet during pregnancy might predispose the offspring to manifestation of metabolic and behavioral disturbances in later life. Western type diet contains large amounts of advanced glycation end products (AGEs). In humans and experimental rodents, intake of AGEs rich diet (AGE-RD) negatively affected glucose homeostasis, and initiated the production of reactive oxygen species. Rats consuming AGE-RD presented changes in behavior. It remains unclear whether maternal intake of AGE-RD might affect developmental plasticity in offspring. We examined early somatic (weight, incisor eruption, ear unfolding, eye opening) and neuromotor development, oxidative status, insulin sensitivity (HOMA index) and locomotor activity assessed in PhenoTyper cages in the offspring of mice fed during pregnancy with either AGE-RD (25% bread crusts/75% control chow) or control chow. Till weaning, somatic development of offspring did not differ between two dietary groups. AGE-RD offspring manifested physiological reflexes (auditory startle, eye lid, ear twitch and righting reflexes) earlier. As young adults, male offspring of AGE-RD dams were heavier and less insulin sensitive compared with their control counterparts. AGE-RD offspring showed higher locomotor activity during the active phase. Our data indicate that maternal AGE-RD during pregnancy might accelerate the maturation of reflexes in offspring, predispose the male progeny to weight gain and affect their glucose homeostasis. These effects manifest without the direct consumption of AGE-RD by offspring. Further work is needed to determine the mechanisms by which maternal AGE-RD affects neurobehavioral pathways in offspring, as well as sex differences in adverse metabolic responses.
... Bazı çalışmalar, MG-modifiye sığır serum albümini kullanarak insülin direnci ve oksidatif stres gelişimine odaklanmıştır. Altı ay boyunca MG-modifiye sığır serum albümini verilen farelerde, oksidatif stres belirteçleri ile MGmodifiye sığır serum albümini suplemantasyonu arasında nedensel bir ilişki saptanmıştır (27). Son yıllarda yapılan bir çalışmada, MG-sığır serum albümin suplemantasyonu alan farelerde dört nesil boyunca insülin direncinin devam ettiği rapor edilmiştir (28). ...
... Cross-sectional studies of healthy subjects and patients undergoing hemodialysis showed a positive relationship between dAGE intake and plasma inflammatory markers. Along with glycoxidation of LDLs by hyperglycemia (Bucala et al. 1994), dAGEs are suspected to bind LDLs after absorption (Cai et al. 2008). dAGEs could increase the rate of oxidized LDLs, leading to vascular toxicity through increasing inflammation and oxidative stress. ...
The main purpose of this review is to clarify whether the consumption of food rich in melanoidins and dietary advanced glycosylation end-products (dAGEs) are harmful or beneficial for human health. There are conflicting results on their harmful effects in the literature, partly due to a methodological issue in how dAGEs are determined in food. Melanoidins have positive functions particularly within the gastrointestinal tract, whereas the intake of dAGEs has controversial physiological consequences. Most of the in vivo intervention trials were done comparing boiled versus roasted diet (low and high dAGE, respectively). However, these studies can be biased by different lipid oxidation and by different calorie density of foods in the two conditions. The attraction that humans have for cooked foods is linked to the benefits they have had during mankind's evolution. The goal for food technologists is to design low-energy-dense products that can satisfy humans' attraction for rewarding cooked foods. Expected final online publication date for the Annual Review of Food Science and Technology Volume 9 is March 25, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... [19][20][21] AGEs are made endogenously 22 and may be absorbed from dietary sources. 23,24 Circulating levels of AGEs appear to correlate between mother and baby, 25 suggesting maternal transmission of AGEs to the fetus. Previous studies have identified that decreasing dietary AGE intake can improve glucose homeostasis in individuals with type 2 diabetes 26 and in healthy, but overweight, adults. ...
The contribution of environmental factors to pancreatic islet damage in type 1 diabetes remains poorly understood. In this study, we crossed mice susceptible to type 1 diabetes, where parental male (CD8(+) T cells specific for IGRP206-214; NOD8.3) and female (NOD/ShiLt) mice were randomized to a diet either low or high in AGE content and maintained on this diet throughout pregnancy and lactation. After weaning, NOD8.3(+) female offspring were identified and maintained on the same parental feeding regimen for until day 28 of life. A low AGE diet, from conception to early postnatal life, decreased circulating AGE concentrations in the female offspring when compared to a high AGE diet. Insulin, proinsulin and glucagon secretion were greater in islets isolated from offspring in the low AGE diet group, which was akin to age matched non-diabetic C57BL/6 mice. Pancreatic islet expression of Ins2 gene was also higher in offspring from the low AGE diet group. Islet expression of glucagon, AGEs and the AGE receptor RAGE, were each reduced in low AGE fed offspring. Islet immune cell infiltration was also decreased in offspring exposed to a low AGE diet. Within pancreatic lymph nodes and spleen, the proportions of CD4(+) and CD8(+) T cells did not differ between groups. There were no significant changes in body weight, fasting glucose or glycemic hormones. This study demonstrates that reducing exposure to dietary AGEs throughout gestation, lactation and early postnatal life may benefit pancreatic islet secretion and immune infiltration in the type 1 diabetic susceptible mouse strain, NOD8.3.
Son yıllarda yapılan çalışmalar diyetle alınan ileri glikasyon son ürünlerinin (AGEs), polikistik over sendromu ile ilişkili hem üreme hem de metabolik işlev bozukluklarında önemli bir rol oynadığını öne sürmektedir. İleri glikasyon son ürünleri, indirgeyici şekerler ile proteinler, lipitler veya nükleik asitler arasındaki enzimatik olmayan glikasyon işlemi tarafından oluşturulan reaktif moleküllerdir. İleri glikasyon son ürünlerinin anahtar hücre içi sinyal yollarının aktivasyonu yoluyla, oksidatif stres ve proinflamatuar sitokinlerin oluşumunu uyararak polikistik over sendromu patogenezine katkıda bulunabilecekleri düşünülmektedir. İleri glikasyon son ürünleri normal metabolik koşullar altında endojen olarak oluşabildikleri gibi özellikle kızartma, fırınlama veya ızgara gibi yüksek sıcaklıklarda pişirilmiş ve işlenmiş besinlerin tüketimiyle de ekzojen olarak da vücuda alınabilmektedir. Polikistik over sendromlu kadınlarda yumurtalık dokusunda anovülasyon ve hiperandrojenizme neden olan yüksek serum AGE seviyeleri bildirilmiştir. Bu derlemede, polikistik over sendromunda metabolik ve üremeyle ilgili değişikliklerin aracıları olarak ileri glikasyon son ürünlerinin rolünün sunulması amaçlanmıştır.
Metabolic syndrome (MS) is a growing disorder affecting thousands of people worldwide, especially in industrialised countries, increasing mortality. Oxidative stress, hyperglycaemia, insulin resistance, inflammation, dysbiosis, abdominal obesity, atherogenic dyslipidaemia and hypertension are important factors linked to MS clusters of different pathologies, such as diabesity, cardiovascular diseases and neurological disorders. All biochemical changes observed in MS, such as dysregulation in the glucose and lipid metabolism, immune response, endothelial cell function and intestinal microbiota, promote pathological bridges between metabolic syndrome, diabesity and cardiovascular and neurodegenerative disorders. This review aims to summarise metabolic syndrome’s involvement in diabesity and highlight the link between MS and cardiovascular and neurological diseases. A better understanding of MS could promote a novel strategic approach to reduce MS comorbidities.
The human body is exposed to dietary advanced glycation end products (AGEs) – dAGEs ingested with food and the endogenous AGEs, which are continuously formed in vivo. Clinical and experimental studies concluded that dAGEs, which are abundant in the Western diet, are directly absorbed in circulation, accumulate in the tissues, and add to the endogenous AGEs to significantly increase the systemic AGEs burden. The interaction between AGEs and the receptor – RAGE – is a key factor in the initiation of intracellular signaling pathways, with the subsequent formation of free radicals and the release of pro-inflammatory cytokines. The pro-inflammatory and prooxidant systemic effects of AGEs promote the development of chronic general diseases. Based on the correlations between AGEs intake, circulatory levels, and the risk of systemic pathology, AGEs measured in the body fluids could be used as biomarkers for the diagnosis and screening of metabolic syndrome and aging. The AGEs-restricted nutrition and physical exercise have beneficial effects and are recommended to promote health across all ages.
Background: Dietary restriction (DR) is a widely used experimental intervention in aging research due to its consistent ability to extend lifespan in most species tested. DR is an all-encompassing term describing interventions that restrict some aspect of nutrition - from calorie amount to calorie type to timing of food intake - and yet share common functional endpoints including extended longevity, but also improvements in healthspan, or the time spent in good health, as well as metabolic fitness and stress resistance. Recent studies highlight the preponderance of sexual dimorphisms in the response to DR and argue for the importance of inclusion of both sexes in preclinical research. OBJECTIVE: We set out to perform a comprehensive assessment of documented health and lifespan outcomes of interventional DR studies in mice that display sexual dimorphism. METHODS: A systematic literature search was conducted according to the PRISMA statement to identify mouse DR studies in which both sexes were included using PubMed. The specific DR interventions examined included calorie restriction (CR), intermittent fasting (IF), protein restriction (PR) and methionine restriction (MetR), with experimental endpoints focused on lifespan and healthspan. RESULTS: Sexual dimorphism in the lifespan and healthspan effects of various DR regimens is a common finding in mice, with the magnitude and direction of dimorphic responses influenced by the specific dietary intervention as well as the strain of mouse used in the study. CONCLUSIONS: Despite the fact that preclinical lifespan and healthspan analyses in mice reveal sexual dimorphism in the response to DR, there is still a large gap in our understanding of how sex affects dietary outcomes. More preclinical research comparing both sexes in the same study with better attention to reporting metrics during peer review and in easily searchable text including title and abstract is required to further our understanding of the impact of sex on health and lifespan in response to DR in rodent studies.
Le vieillissement massif de la population et le bond incroyable ces dernières décennies de l’espérance de vie ont entraîné une prise de conscience de l’importance de ce problème. La nécessité de mieux appréhender les mécanismes du vieillissement est devenue une urgence de santé publique. De nombreux groupes de recherche se consacrent depuis quelques années à l'identification de gènes et de voies de signalisation impliqués dans le processus du vieillissement. Ce processus biologique, qui touche chaque espèce et chaque individu de manière spécifique, se caractérise par un déclin graduel de la fonction de nombreux processus physiologiques en fonction de l’âge. Toutefois même s’il est inéluctable, le vieillissement est influençable. En effet, de nombreux facteurs, autant intrinsèques (facteurs génétiques, télomérases, stress oxydatif), qu’extrinsèques (hygiène de vie, pollution, alimentation) vont influencer le vieillissement. C’est d’ailleurs un facteur de risque important dans le développement de nombreuses pathologies associées à l’âge (le diabète de type II, le cancer, les maladies neurodégénératives, les maladies cardiovasculaires). De plus, il a déjà été démontré dans la littérature que la modulation d’un seul gène peut influencer, autant positivement que négativement, le vieillissement d’un individu. Plus que l’allongement de la durée de vie, c’est une durée de vie sans déficience (concept du « bien vieillir ») qui fait l’objet des principales recherches. Les gènes ayant des effets sur ce processus sont habituellement des gènes jouant un rôle important dans une voie de signalisation et donc, sont souvent conservés à travers l’évolution. Les travaux décrits dans cette thèse concernent l’implication d’un nouveau snoARN (jouvence), requis dans l’épithélium de l’intestin, dans les mécanismes du vieillissement de la drosophile. Ils ont en particulier révélé la capacité de ce snoARN à augmenter de manière spectaculaire la durée de vie des mouches en enrayant les mécanismes du vieillissement et en luttant contre les effets délétères associés. jouvence permettrait ainsi de lutter contre les maladies associées à la vieillesse telles que la neurodégénérescence, l’hyperplasie intestinale, mais également contre les troubles métaboliques, tout en prolongeant la durée de vie de l’organisme. Il serait impliqué dans différentes voies métaboliques pouvant avoir un impact sur la santé à long terme des drosophiles. jouvence semble réguler le métabolisme lipidique, l’homéostasie intestinale, ainsi que la résistance au stress. Par contre, son inactivation de provoque des effets néfastes qui mènent à la dégradation rapide de plusieurs fonctions métaboliques et à la mort prématurée des mouches. Les résultats obtenus dans cette étude dévoilent un lien entre jouvence et le contrôle du vieillissement en santé chez la drosophile.
Human food is composed of loads of chemicals derived naturally as well as unintentionally through environmental sources. Food additives added purposefully, play an important role in the palatability of foods. Most additives are synthetic whose essentiality in food processing is well-known however their health risks are not overlooked. The palatability of food should not only stimulate our eating desire alone but, also assure sufficient quality and safety. Application of food additives varies from region to region due to cultural or ethnic differences and the local food availability. There are about more than ten thousand chemicals allowed in food whereas due to weak enforcement, it becomes onerous for regulatory bodies identifying chemicals that are inadequately or not tested at all for safety. The hiking population and urbanization in many industrialized and developing countries resulted in life-style changes including culinary and eating choices. Particularly, the modern way of this globalised life demands ready-to-cook or ready-made foods, snacks, sweets, soft drinks, desserts, confectionery and so on. These sorts of food would be most uninteresting unless processed with additives. This puts food industries under demand to robustly supply foods that are either partially, fully or ultra-processed using plenty of additives. Recent research warns consuming food additives may result in serious health risks, not only for children but also for adults. Growing body of studies on food additives in various experimental animals, cell cultures, and human population suggest elevation of number of obesity and diabetes risk factors i.e. adiposity, dyslipidemia, weight gain, hyperglycaemia, insulin resistance, glucose intolerance, energy imbalance, hormonal intervention etc. Hence, it is important to identify and explore food obesogens or obesogenic food additives posing potential impact. Based on the recent toxicological findings, the review aspires to establish the association between exposure of food obesogen and metabolic disruption which may help filling knowledge gaps and distributing more knowledge, awareness and effective measures to implement treatment and preventive strategies for metabolic syndrome.
Various harmful Maillard reaction products such as lactulosyl-lysine (furosine), furfurals, and advanced glycation end products (AGEs) could be formed during the thermal processing of dairy products, which could lead to various chronic diseases. In this review, the furosine, furfurals, and AGEs formation, occurrence, analysis methods, and toxicological and health aspects in various dairy products were summarized to better monitor and control the levels of harmful Maillard reaction products in processed dairy products. It was observed that all types of dairy products, including raw milk, contain harmful Maillard reaction products, with the highest in whey cheese and condensed milk. High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the common method for the determination of furosine and furfurals and AGEs in dairy products, respectively. However, the simple, rapid, environment-friendly, and accurate methods of determination are still to be developed. Incorporating resveratrol, pectin oligosaccharides (POS) in milk are effective methods to inhibit AGEs formation. This review provides a guide not only for consumers regarding the selection and consumption of dairy products, but also for monitoring and controlling the quality of dairy products.
Nefroloji, temel olarak böbrek hastalıklarıyla ilgilenen bir tıp bilimi dalıdır. Nephros böbrekler, -ology çalışma anlamına gelen Yunanca kökenli bir terimdir. Türkçede böbrek kelimesinin kökeni araştırıldığında, Orhun Yazıtlarında kaburga ve kalça arasındaki boşluğun adının “bögür” olarak geçtiği görülür. Uygurca tıp metinlerindeki kullanımı bügür’dür. Eski Türkçeden beri kullanılagelen bögür kelimesi “böbrek, böğür, yan” anlamındadır. Türkçenin tarihi dönemlerinde, Karahanlıcada bögür, Çağataycada ise bögr şeklindedir. Dîvânu Lugâti't-Türk’te (1070, Kaşgarlı Mahmut) bögür, böbrek adı olarak geçmektedir. 1400’den önce Osmanlı Döneminde muhtemelen böğür kelimesine -ek eki getirilerek böğrek kelimesi böbrek anlamında kullanılmıştır. Halk arasında hâlâ organın bulunduğu yerle ilişkilendirilmek için böğür kelimesi yaygın kullanılsa da, günümüzde artık böbrek olarak ifade edilmektedir.
Günümüzde epidemiyolojik çalışmalar, böbreklerimizi olumsuz etkilediğini bildiğimiz diabetes mellitus, hipertansiyon, obezite, aterosklerotik kalp hastalığı, romatolojik hastalıklar ve kanser gibi sağlık problemlerinin sıklığının giderek arttığını göstermektedir. Ayrıca bunlara primer böbrek hastalıkları ve sekonder olarak böbreği tutan başka birçok sistemik hastalığı da ekleyince günlük hekimlik pratiğinde böbrek rahatsızlığı şüphesi olan ya da bu tanı ile tedavi-izlem altında olan bir çok hasta ile karşılaşmaya devam edeceğimizi öngörebiliriz.
Böbrekler sıvı, elektrolit, asit ve baz dengesini düzenleyen, ilaçlar ve toksinler dahil bir çok endojen ve eksojen atık ürünleri ve fazla sıvıyı kandan filtreleyen karmaşık kan damarı ve tübül ağına sahip boşaltım sisteminin yaşam için hayati önem taşıyan organıdırlar. Nefroloji uzmanları; böbrek yetmezliği, hipertansiyon, elektrolit (sodyum, potasyum, kalsiyum, fosfor vb.) bozuklukları ve idrar anormalliklerinin (hematüri ve proteinüri vb.) nedenlerinin araştırılması, tedavi ve takibi, ayrıca kullandığımız ilaçlara bağlı böbrek toksisitesinin olumsuz etkilerinin önlenmesi konularında rol alırlar.
Kronik böbrek hastalığı dünyada ve Türkiye’de giderek artan önemli bir halk sağlığı sorunu haline gelmiştir. Böbrek hastalığı farkındalığını arttırmak için Uluslararası Nefroloji Derneği (ISN) ile Uluslararası Böbrek Vakıfları Federasyonunun (IFKF) ortak girişimiyle 9 Mart 2006 tarihinde ilk kez “Dünya Böbrek Günü” kutlanmıştır ve o günden bu yana her yıl Mart ayının 2. perşembe günü tüm dünyada “Dünya Böbrek Günü” olarak kutlanmaya devam edilmektedir. Kronik böbrek hastalığının en önemli nedeni diabetes mellitustur. Ülkemizde yapılan taramalara göre erişkinlerde kronik böbrek hastalığı sıklığı %15.7 (~7.5 milyon kişi), böbrek hastalıklarının farkındalığı ise %1.6 düzeyinde tahmin edilmekte ve sorunun boyutunun tahmin edilenin çok üzerinde olduğu görülmektedir. Hâlen tüm dünyada 2 milyondan fazla kişi diyalize girmekte ve böbrek nakli tedavileri ile yaşamını sürdürmektedir. Önümüzdeki 10 yıl içinde bu sayının ikiye katlanacağı, tedavi maliyetlerinin 1.5 trilyon doları aşacağı hesaplanmaktadır. Dolayısıyla temel olarak böbrek sağlığımızı korumak için gerekli önlemleri almak, yani koruyucu hekimlik her zaman daha önemlidir. Kronik böbrek hastalığından korunmak için bireyler; düzenli egzersiz yapmalı, sağlıklı beslenmeli, vücut ağırlığını korumalı, tuzu azaltmalı, yeterli sıvı almalı, sigara içmemeli, alkolden uzak durmalı, ağrı kesici ilaçlardan hekim önerisi olmadığı sürece kaçınmalı, kan basıncını ve kan glukozunu düzenli olarak ölçtürmeli ve risk grubunda ise böbreklerini düzenli olarak kontrol ettirmelidirler.
Diğer mesleklerden insan sağlığı ile uğraştığı için daha kutsal sayılan hekimlik mesleğinin bir diğer özelliği ise sürekli yenilenme ihtiyacının olmasıdır. Modern tıp çağında teşhis ve tanı yöntemleri, görüntüleme teknikleri, cerrahi ve robotik müdahaleler, girişimsel işlemler, özellikle moleküler düzeydeki bilimsel gelişmeler yaygınlaşmaktadır. Bununla birlikte hastadan anamnez almanın ve muayene etmenin yani hastayı dinlemenin, yakınmalarını doğru yorumlamanın ilk önceliğimiz olduğu unutulmamalıdır. Çünkü Hipokrat hekimliği döneminden beri “Hastalık yoktur, hasta vardır.” ilkesi hiç değişmemiştir. Böbrek hastalıklarında da, hastalığın özelliği olan semptom ve bulgular hiçbir zaman hastalar arasında aynı ölçüde görülmemektedir.
Thermal processing is one of the most important processing methods in the food industry. However, many studies have revealed that thermal processing can have detrimental effects on the nutritional and functional properties of foods because of the complex interactions among food components. Proteins are essential nutrients for humans, and changes in the structure and nutritional properties of proteins can substantially impact the biological effects of foods. This review focuses on the interactions among proteins, sugars, and lipids during thermal food processing and the effects of these interactions on the structure, nutritional value, and biological effects of proteins. In particular, the negative effects of modified proteins on human health and strategies for mitigating these detrimental effects from two perspectives, namely, reducing the formation of modified proteins during thermal processing and dietary intervention in vivo, are discussed.
Electrophilic compounds present in humans, originating from endogenous processes or pollutant exposures, pose a risk to health though their reaction with nucleophilic sites in protein and DNA. Among this chemical class, aldehydes are mainly present in indoor air and they can also be produced by endogenous lipid peroxidation arising from oxidative stress. Known to be very reactive, aldehydes have the ability to form exocyclic adducts to DNA that, for the most if not repaired correctly, are mutagenic and by consequence potential agents involved in carcinogenesis. The aim of this work was to establish profiles of exocyclic DNA adducts induced by aldehyde mixtures, which could ultimately be considered as a genotoxic marker of endogenous and environmental aldehyde exposure. Adducts were quantified by an accurate, sensitive and validated ultra high performance liquid chromatography-electrospray ionization analytical method coupled to mass spectrometry in the tandem mode (UHPLC-ESI-MS/MS). We simultaneously measured 9 exocyclic DNA adducts generated during the exposure in vitro of calf thymus DNA to different concentrations of each aldehyde along, as well as, to an equimolar mixture of these aldehydes. This approach has enabled us to establish dose-response relationships that allowed displaying the specific reactivity of aldehydes towards corresponding adducts formation. Profiles of these adducts determined in DNA of current smokers and nonsmokers blood samples supported these findings. These first results are encouraging to explore genotoxicity induced by aldehyde mixtures and can furthermore be used as future reference for adductomic approaches.
Insulin resistance, which is caused by the long-term consumption of high-calorie diet, sedentary lifestyle and obesity, and predisposition to genetic and environmental factors. The pathogenesis of insulin resistance and ischemic stroke is very complex. It not only involves hyperglycemia blood coagulation, atherosclerosis, and aberrations in blood pressure regulation, but also changes in lipid metabolism, endothelial function, low-grade inflammation, smooth muscle cell proliferation, and fibrinolysis. Insulin resistance also enhances platelet adhesion, activation, and aggregation which are conducive to the occurrence of ischemic stroke.
De nombreuses études dans la seconde moitié du 20ème siècle, ont mis en évidence que des génotoxiques cancérogènes réagissent avec l'ADN pour former par liaison covalente des adduits qui sont impliqués dans le processus cancérigène. Bien qu’il existe des preuves convaincantes de la présence de multiples adduits à l'ADN dans les poumons de sujets exposés au tabagisme ou en milieu professionnel à un aldéhyde donné, il est évident que c'est un domaine dans lequel des recherches supplémentaires ont été nécessaires. L’objectif de ce travail de thèse est d’établir des profils d’adduits exocycliques à l'ADN induits par le mélange d’aldéhydes, qui pourraient à terme être considérés comme un marqueur génotoxique de l’exposition aux aldéhydes, tant endogène qu’environnemental. Pour cette raison, nous avons validé une méthode en UHPLC-MS/MS rapide, sensible et précise en utilisant la dilution isotopique, pour la quantification à l’état de trace de 9 adduits exocycliques à l’ADN dérivés de 8 principaux aldéhydes exogènes et endogènes, notamment le formaldéhyde, l’acétaldéhyde, l’acroléine, le crotonaldéhyde, le malondialdéhyde, le 4-hydroxy-2-nonénal, le glyoxal et le méthylglyoxal. Ces adduits ont été synthétisés et purifiés ainsi que leurs homologues marqués au 13C10, 15N5, identifiés et quantifiés par le biais des courbes d'étalonnage allant de 0,25 à 250 ng/mL d'adduits dans l'eau et l'ADN afin de décrire les effets matrice. Des échantillons de contrôle qualité ont été préparés et analysés afin de vérifier l'exactitude et la précision de la méthode dans des situations de répétabilité et de fidélité intermédiaire. L'absence de contamination croisée a également été démontrée. La méthode est capable de différencier les 9 analytes d'intérêt et leurs étalons internes en utilisant pour chaque analyte une transition de quantification et une seconde de confirmation. Cette méthode a été validée selon les recommandations de l'Agence Européenne des Médicaments concernant les méthodes bioanalytiques. Elle répond à tous les critères essentiels pour garantir l'acceptabilité des performances et la fiabilité des résultats d'analyse. Cette méthode est la toute première validée et peut être utilisée en adductomique dans le cadre d'études sur l'exposome. En plus, nous avons simultanément mesuré par une approche in vitro les 9 adduits exocycliques dans de l’ADN de thymus de veau exposé à de différentes concentrations de chaque aldéhyde seul ou en mélanges équimolaires. Cette approche nous a permis d’établir des relations dose-dépendantes pour tous les aldéhydes à l’exception du malondialdéhyde et du méthylglyoxal. Une relation dose-réponse a également été observée avec les mélanges équimolaires d’aldéhydes. Elle a permis de définir des réactivités différentes des aldéhydes en mélange vis-à-vis de l’ADN. Les profils de ces adduits exocycliques ont été également déterminés dans l'ADN de sang de fumeurs et de non-fumeurs. La fumée de cigarette contient plusieurs aldéhydes connus de se lier par covalence aux bases de l’ADN, ainsi l’adduit à l’ADN peut être considéré comme biomarqueur d’exposition au tabac. Des différences significatives dans les niveaux d’adduits ont été obtenues entre l’ADN des fumeurs et celui des non-fumeurs à l’exception de l’adduit induit par le malondialdéhyde. Des corrélations ont été établies entre chaque adduit et les marqueurs de la consommation tabagique sans aucune corrélation significative de la totalité des adduits avec un marqueur spécifique. Par ailleurs, nous avons montré que l’exposition au formaldéhyde, au butanal et au benzaldéhyde a eu un effet sur les concentrations du MDA urinaire mesurées chez les policiers libanais stationnés au carrefour pendant 7 h par jour et après exposition de 5 jours aux émissions du trafic routier. Une augmentation du MDA plasmatique a été décrite ; les années de travail avaient une incidence sur les concentrations de ce biomarqueur.
Obesity, a chronic multifaceted disease, predisposes its patients to increased risk of metabolic disorders such as: diabetes mellitus, cardiovascular diseaseas, dyslipidemia, etc. Recent studies reported it to be amongst the leading causes of deaths in the world. Although several treatment options for obesity abound, many of them have not been able to successfully reverse the existing obesity and metabolic dysregulation. This has therefore warranted the need for either alternative therapies or diversification of the treatment approach for obesity and its comorbidity. When the receptor for advanced glycation end products (RAGE) interacts with its ligand, RAGE-ligand, an inflammatory signaling cascade is activated, which leads to the activation of nuclear factor kappa B (NF-kB) and transcription of inflammatory cytokines. This action has been associated with the development of obesity and its mediated metabolic dysregulation. In view of the increasing prevalence of obesity globally and the potential threat it places on life expectancy, this article reviewed the promising potentials of targeting endogenous secretory receptor for advanced glycation end products/soluble receptors for advanced glycation end products signaling as a treatment approach for obesity. We carried out a literature search in several electronic data bases such as: Pubmed, Pubmed Central, Google, Google Scholar, Scopus and Medline from 1980 to 2019 to acquire the status of information concerning this concept. The article suggests the need for the development of an esRAGE/sRAGE targeted pharmacotherapy as a treatment approach for obesity and its comorbidity.
The heat-based spray drying process generating the highest level of advanced glycation end-products (AGEs) in the infant formula processing was set as a control point from which the levels of AGE markers, N-carboxymethyllysine, 5-hydroxymethylfurfural, and fluorescence intensity, can be mitigated. We optimized the parameters, including inlet temperature, feeding rate, and aspirator rate during spray drying, and alternatively optimized food additives, including pyridoxine hydrochloride, dl-α-tocopheryl acetate, and l-carnitine. Using response surface methodology, the optimal condition based on our experimental condition for the inlet temperature, pump rate, and aspirator rate were 148.7 °C, 342.4 mL/h and 28.6 m³/h, respectively, and the optimal conditions of pyridoxine hydrochloride, dl-α-tocopheryl acetate and l-carnitine were 0.99 mg/100 g dry mass (DM), 8 mg/100 g DM and 20.4 mg/100 g DM, respectively. These results suggest that AGEs can be mitigated by controlling the parameters and optimizing the addition of food additives during the spray-drying process.
Back pain is a leading cause of disability and is strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structure-modifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat. Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates, yet it is unclear whether dietary AGEs can cross the endplates to accumulate in IVDs. A dietary mouse model was used to test the hypothesis that chronic consumption of high AGE diets results in sex-specific IVD structural disruption and functional changes. High AGE diet resulted in AGE accumulation in IVDs and increased IVD compressive stiffness, torque range and failure torque, particularly for females. These biomechanical changes were likely caused by significantly increased AGE crosslinking in the annulus fibrosus, measured by multiphoton imaging. Increased collagen damage measured with collagen hybridizing peptide did not appear to influence biomechanical properties and may be a risk factor as these animals age. The greater influence of high AGE diet on females is an important area of future investigation that may involve AGE receptors known to interact with estrogen. We conclude that high AGE diets can be a source for IVD crosslinking and collagen damage known to be important in IVD degeneration. Dietary modifications and interventions that reduce AGEs warrant further investigation and may be particularly important for diabetics, in whom AGEs accumulate more rapidly.
Membrane damage via Maillard reaction products of half-fin anchovy hydrolysates and glucose (designated as HAHp(9.0)-G MRPs) was evaluated using an in vitro Escherichia coli (E. coli) model. The incubation of HAHp(9.0)-G MRPs led to a significant increase of outer and inner membrane permeability. Furthermore, membrane integrity was seriously destroyed, as observed by scanning electron microscopy and indicated by decreased fluorescence signal of 4’, 6-diamidino-2-phenylindole stain. Interestingly, HAHp(9.0)-G MRPs induced significant hydrogen peroxide (H2O2) production in E. coli after 3 h incubation, which contributed to the antibacterial activity of HAHp(9.0)-G MRPs. As one of the reactive oxygen species, excess H2O2 in vivo might impair the antioxidant balance. Therefore, the oxidative status of healthy mice after short-term intake of HAHp(9.0)-G MRPs was investigated. After HAHp(9.0)-G MRPs administration at low dose (0.1 g/kg•d•body weight) and high dose (1.0 g/kg•d•body weight) for 14 days, the body weight of female mice decreased, and the body weight of male mice increased. However, the HAHp(9.0)-G MRPs administration did not affect the hepatic antioxidant defense for either female or male mice. Some positive responses, like increased superoxidase dismutase (SOD) and glutathione peroxidase (GPx) as well as decreased lipid peroxidation (LPO) content, were detected, especially in liver. Though decrease of catalase activity indicated glycation compounds from HAHp(9.0)-G MRPs might be absorbed in vivo, the lower SOD/GPx ratios of HAHp(9.0)-G MRPs fed groups than the normal groups also suggested HAHp(9.0)-G MRPs administration could reduce LPO stress in mice. Therefore, the healthy animals generated higher antioxidant status during the experimental period.
The reaction of sugars, such as glucose and glyceraldehyde, with amino groups of proteins and lipids is enhanced under hyperglycemic conditions. As a result, the formation and accumulation of senescent macroprotein derivatives called advanced glycation end products (AGEs) have been known to progress in diabetes. Modification of proteins by AGEs alters their tertiary structure and physiological function, thereby causing multiple organ damage in diabetes. Further, engagement of the cell surface receptor RAGE with AGEs evokes oxidative stress and inflammatory reactions in a variety of tissues, being involved in the development and progression of numerous diabetes-associated disorders, including cardiovascular disease, osteoporosis, Alzheimer’s disease, and cancer growth and metastasis. In this chapter, I briefly review the pathophysiological role of AGEs and their receptor RAGE system in diabetes- and aging-related complications, especially focusing on cardiovascular disease and osteoporosis.
Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.
The Maillard reaction, a non-enzymatic reaction of ketones and aldehydes with amino groups of proteins, contributes to the aging of proteins and to complications associated with diabetes. Methylglyoxal (MG) is a 2-oxoaldehyde derived from glycolytic intermediates and produced during the Maillard reaction. We reported previously the formation of a lysine-lysine protein cross-linking structure (imidazolysine) and a fluorescent arginine modification (argpyrimidine) from the Maillard reaction of MG. Here we show that rabbit antibodies to MG-modified ribonuclease A identify proteins modified by the Maillard reaction of glucose, fructose, ribose, glyceraldehyde, glyoxal, ascorbate, and ascorbate oxidation products (dehydroascorbate, 2,3-diketogulonate, L-xylosone, and L-threose) in addition to those modified by MG. The antibody recognized imidazolysine and argpyrimidine and a glyoxal-derived lysine-lysine cross-link. It did not react with Nepsilon-carboxymethyllysine. Incubations with amino acids revealed strongest reactivity with Nalpha-t-butoxycarbonylarginine and MG, and we identified argpyrimidine as one of the epitopes from this incubation mixture. Serum proteins from human diabetics reacted more strongly with the antibody than those from normal individuals, and the levels correlated with glycemic control. Collagen from human corneas contained MG-derived modifications, with those from older subjects containing higher levels of modified proteins than those from younger ones. An immunoaffinity-purified antibody showed higher reactivity with old corneas than with younger ones and localized the antigens primarily within the stromal region of the cornea. These results confirm reported MG-derived modifications in tissue proteins and show that dicarbonyl-mediated protein modification occurs during Maillard reactions in vivo.
Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.
Human aging is impacted severely by cardiovascular disease and significantly but less overtly by renal dysfunction. Advanced glycation endproducts (AGEs) have been linked to tissue damage in diabetes and aging, and the AGE inhibitor aminoguanidine (AG) has been shown to inhibit renal and vascular pathology in diabetic animals. In the present study, the effects of AG on aging-related renal and vascular changes and AGE accumulation were studied in nondiabetic female Sprague-Dawley (S-D) and Fischer 344 (F344) rats treated with AG (0.1% in drinking water) for 18 mo. Significant increases in the AGE content in aged cardiac (P < 0.05), aortic (P < 0.005), and renal (P < 0.05) tissues were prevented by AG treatment (P < 0.05 for each tissue). A marked age-linked vasodilatory impairment in response to acetylcholine and nitroglycerine was prevented by AG treatment (P < 0.005), as was an age-related cardiac hypertrophy evident in both strains (P < 0.05). While creatinine clearance was unaffected by aging in these studies, the AGE/ creatinine clearance ratio declined 3-fold in old rats vs. young rats (S-D, P < 0.05; F344, P < 0.01), while it declined significantly less in AG-treated old rats (P < 0.05). In S-D but not in F344 rats, a significant (P < 0.05) age-linked 24% nephron loss was completely prevented by AG treatment, and glomerular sclerosis was markedly suppressed (P < 0.01). Age-related albuminuria and proteinuria were markedly inhibited by AG in both strains (S-D, P < 0.01; F344, P < 0.01). These data suggest that early interference with AGE accumulation by AG treatment may impart significant protection against the progressive cardiovascular and renal decline afflicting the last decades of life.
Endogenous advanced glycation endproducts (AGEs) include chemically crosslinking species (glycotoxins) that contribute to the vascular and renal complications of diabetes mellitus (DM). Renal excretion of the catabolic products of endogenous AGEs is impaired in patients with diabetic or nondiabetic kidney disease (KD). The aim of this study was to examine the oral absorption and renal clearance kinetics of food AGEs in DM with KD and whether circulating diet-derived AGEs contain active glycotoxins. Thirty-eight diabetics (DM) with or without KD and five healthy subjects (NL) received a single meal of egg white (56 g protein), cooked with (AGE-diet) or without fructose (100 g) (CL-diet). Serum and urine samples, collected for 48 hr, were monitored for AGE immunoreactivity by ELISA and for AGE-specific crosslinking reactivity, based on complex formation with 125I-labeled fibronectin. The AGE-diet, but not the CL-diet, produced distinct elevations in serum AGE levels in direct proportion to amount ingested (r = 0.8, P < 0.05): the area under the curve for serum ( approximately 10% of ingested AGE) correlated directly with severity of KD; renal excretion of dietary AGE, although normally incomplete (only approximately 30% of amount absorbed), in DM it correlated inversely with degree of albuminuria, and directly with creatinine clearance (r = 0.8, P < 0.05), reduced to <5% in DM with renal failure. Post-AGE-meal serum exhibited increased AGE-crosslinking activity (two times above baseline serum AGE, three times above negative control), which was inhibited by aminoguanidine. In conclusion, (i) the renal excretion of orally absorbed AGEs is markedly suppressed in diabetic nephropathy patients, (ii) daily influx of dietary AGEs includes glycotoxins that may constitute an added chronic risk for renal-vascular injury in DM, and (iii) dietary restriction of AGE food intake may greatly reduce the burden of AGEs in diabetic patients and possibly improve prognosis.
Nepsilon-(Carboxymethyl)lysine (CML) is a stable chemical modification of proteins formed from both carbohydrates and lipids during autoxidation reactions. We hypothesized that carboxymethyl lipids such as (carboxymethyl)phosphatidylethanolamine (carboxymethyl-PE) would also be formed in these reactions, and we therefore developed a gas chromatography-mass spectrometry assay for quantification of carboxymethylethanolamine (CME) following hydrolysis of phospholipids. In vitro, CME was formed during glycation of dioleoyl-PE under air and from linoleoylpalmitoyl-PE, but not from dioleoyl-PE, in the absence of glucose. In vivo, CME was detected in lipid extracts of red blood cell membranes, approximately 0.14 mmol of CME/mol of ethanolamine, from control and diabetic subjects, (n = 22, p > 0.5). Levels of CML in erythrocyte membrane proteins were approximately 0.2 mmol/mol of lysine for both control and diabetic subjects (p > 0.5). For this group of diabetic subjects there was no indication of increased oxidative modification of either lipid or protein components of red cell membranes. CME was also detected in fasting urine at 2-3 nmol/mg of creatinine in control and diabetic subjects (p = 0.085). CME inhibited detection of advanced glycation end product (AGE)-modified protein in a competitive enzyme-linked immunosorbent assay using an anti-AGE antibody previously shown to recognize CML, suggesting that carboxymethyl-PE may be a component of AGE lipids detected in AGE low density lipoprotein. Measurement of levels of CME in blood, tissues, and urine should be useful for assessing oxidative damage to membrane lipids during aging and in disease.
We tested the theory that reactive oxygen species cause aging. We augmented the natural antioxidant systems of Caenorhabditis elegans with small synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type worms increased their mean life-span by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their life-span (a 67 percent increase). It appears that oxidative stress is a major determinant of life-span and that it can be counteracted by pharmacological intervention.
Advanced glycation end products (AGEs), known promoters of diabetic complications, form abundantly in heated foods and are ingested in bioreactive forms. To test whether dietary AGEs play a role in the progression of insulin resistance, C57/BL/KsJ db/db mice were randomly placed for 20 weeks on a diet with either a low AGE content (LAD) or a 3.4-fold higher content of AGE (high AGE diet [HAD]), including (epsilon)N-carboxymethyllysine (CML) and methylglyoxal (MG). LAD-fed mice showed lower fasting plasma insulin levels throughout the study (P = 0.01). Body weight was reduced by approximately 13% compared with HAD-fed mice (P = 0.04) despite equal food intake. LAD-fed mice exhibited significantly improved responses to both glucose (at 40 min, P = 0.003) and insulin (at 60 min, P = 0.007) tolerance tests, which correlated with a twofold higher glucose uptake by adipose tissue (P = 0.02). Compared with the severe hypertrophy and morphological disorganization of islets from HAD-fed mice, LAD-fed mice presented a better-preserved structure of the islets. LAD-fed mice demonstrated significantly increased plasma HDL concentrations (P < 0.0001). Consistent with these observations, LAD-fed mice exhibited twofold lower serum CML and MG concentrations compared with HAD-fed mice (P = 0.02). These results demonstrate that reduced AGE intake leads to lower levels of circulating AGE and to improved insulin sensitivity in db/db mice.
The general increase in reactive oxygen species generated from glucose-derived advanced glycation endproducts (AGEs) is among the key mechanisms implicated in tissue injury due to diabetes. AGE-rich foods could exacerbate diabetic injury, at least by raising the endogenous AGE.
Herein, we tested whether, prior to ingestion, diet-derived AGEs contain species with cell activating (TNFalpha), chemical (cross-linking) or cell oxidative properties, similar to native AGEs. Glutathione (GSH) and GSH peroxidase (GPx) were assessed after exposure of human umbilical vein endothelial cell (HUVECs) to affinity-purified food-AGE extracts, each exposed to 250 degrees C, for 10 min, along with synthetic AGEs.
Animal product-derived AGE, like synthetic methylglyoxal-bovine serum albumin (MG-BSA), AGE-BSA, and AGE-low density lipoprotein (AGE-LDL), induced a dose- and time-dependent depletion of GSH (()60-75%, p, 0.01) and an increase in GPx activity (()500-600%, p < 0.01), consistent with marked TNFalpha and cross-link formation (p < 0.05); this contrasted with the low bioreactivity of starch/vegetable AGE-extracts, which was similar to that of control BSA and CML- BSA and BSA (p:NS). Anti-AGE-R1,2,3 and -RAGE IgG each inhibited cell-associated (125) I-dAGE by approximately 30-55%; GSH/GPx were effectively blocked by N-acetyl-cysteine (NAC, 800 uM, p < 0.01) and aminoguanidine-HCl (AG, 100 uM, p < 0.01).
Thus, food-derived AGE, prior to absorption, contain potent carbonyl species, that can induce oxidative stress and promote inflammatory signals.
The aim of this study was to determine in humans whether oxidized cholesterol in the diet is absorbed and contributes to the pool of oxidized lipids in circulating lipoproteins. When a meal containing 400 mg cholestan-5α,6α-epoxy-3β-ol (α-epoxy cholesterol) was fed to six controls and three subjects with Type III hyperlipoproteinemia, α-epoxy cholesterol in serum was found in chylomicron/chylomicron remnants (CM/RM) and endogenous (VLDL, LDL, and HDL) lipoproteins. In controls, α-epoxy cholesterol in CM/RM was decreased by 10 h, whereas in endogenous lipoproteins it remained in the circulation for 72 h. In subjects with Type III hyperlipoproteinemia, α-epoxy cholesterol was mainly in CM/RM. In vitro incubation of the CM/RM fraction containing α-epoxy cholesterol with human LDL and HDL that did not contain α-epoxy cholesterol resulted in a rapid transfer of oxidized cholesterol from CM/RM to both LDL and HDL. In contrast, no transfer was observed when human serum was substituted with rat serum, suggesting that cholesteryl ester transfer protein is mediating the transfer. Thus, α-epoxy cholesterol in the diet is incorporated into the CM/RM fraction and then transferred to LDL and HDL, contributing to lipoprotein oxidation. Moreover, LDL containing α-epoxy cholesterol displayed increased susceptibility to further copper oxidation in vitro.
It is possible that oxidized cholesterol in the diet accelerates atherosclerosis by increasing oxidized cholesterol levels in circulating LDL and chylomicron remnants.
Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66(Shc-/-) and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66(Shc-/-) mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% high-fat treatment increased the aortic cumulative early lesion area by approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice. Early lesions from p66(Shc-/-) mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66(Shc-/-) may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66(Shc) might represent a molecular target for therapies against vascular diseases.
A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.
Advanced glycation end products (AGEs) are implicated in beta-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD- and insulin-responsive interferon (IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition.
For more than 60 years the only dietary manipulation known to retard aging was caloric restriction, in which a variety of species respond to a reduction in energy intake by demonstrating extended median and maximum life span. More recently, two alternative dietary manipulations have been reported to also extend survival in rodents. Reducing the tryptophan content of the diet extends maximum life span, while lowering the content of sulfhydryl-containing amino acids in the diet by removing cysteine and restricting the concentration of methionine has been shown to extend all parameters of survival, and to maintain blood levels of the important anti-oxidant glutathione. To control for the possible reduction in energy intake in methionine-restricted rats, animals were offered the control diet in the quantity consumed by rats fed the low methionine diet. Such pair-fed animals experienced life span extension, indicating that methionine restriction-related life span extension is not a consequence of reduced energy intake. By feeding the methionine restricted diet to a variety of rat strains we determined that lowered methionine in the diet prolonged life in strains that have differing pathological profiles in aging, indicating that this intervention acts by altering the rate of aging, not by correcting some single defect in a single strain.
Advanced glycation endproducts (AGE) contribute to kidney disease due to diabetes or aging by means of mesangial cell (MC) receptors, such as the receptor for AGE (RAGE), which promote oxidant-stress-dependent NF-κB activation and inflammatory gene expression. MC also express scavenger receptors SR-I and SR-II and AGE receptors 1, 2, and 3 (AGE-R1, -R2, and -R3), some of which are linked to AGE turnover. Because AGE-R1 expression is found suppressed in severe diabetic kidney disease, as other receptors increase, we investigated whether his molecule has a protective role against AGE-induced MC injury. A stable murine MC line overexpressing AGE-R1 (R1-MC) was generated, exhibiting a 1.8- to 2.7-fold increase in ¹²⁵I-AGE-specific binding, uptake, and degradation, compared with mock-MC. However, AGE-stimulated NF-κB activity and mitogen-activated protein kinase (MAPK) (p44/42) phosphorylation were found markedly suppressed in R1-MC. Additionally, AGE-stimulated macrophage chemotaxis protein 1 and RAGE overexpression were abolished in R1-MC. The effect of R1 on RAGE signaling was investigated after overexpressing RAGE in Chinese hamster ovary cells, which lack RAGE. AGE stimulation elicited NF-κB and MAPK activities in RAGE-Chinese hamster ovary cells; however, after cotransfection with R1, these responses were suppressed. Also, after silencing endogenous R1 in wild-type MC by R1 small interfering RNA, AGE-mediated MAPK/p44/42 activation exceeded by >2-fold that of mock-MC, consistent with loss of the activation-inhibitory properties of native AGE-R1. AGE-R1, although enhancing AGE removal, is also a distinct receptor in that it suppresses AGE-mediated MC inflammatory injury through negative regulation of RAGE, a previously uncharacterized pathway that may protect renal and other tissue injury due to diabetes and aging.
• oxidant stress
• glycoxidation
• NF-κB
• extracellular signal-regulated kinase 1/2
• nephropathy
To determine the role of reactive oxygen species in mammalian longevity, we generated transgenic mice that overexpress human catalase localized to the peroxisome, the nucleus, or mitochondria (MCAT). Median and maximum life spans were maximally increased (averages of 5 months and 5.5 months, respectively) in MCAT animals. Cardiac pathology and cataract development were delayed, oxidative damage was reduced, H2O2 production and H2O2-induced aconitase inactivation were attenuated, and the development of mitochondrial deletions was reduced. These results support the free radical theory of aging and reinforce the importance of mitochondria as a source of these radicals.
Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(++) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db(++) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.
p66(Shc) regulates both steady-state and environmental stress-dependent reactive oxygen species (ROS) generation. Its deletion was shown to confer resistance to oxidative stress and protect mice from aging-associated vascular disease. This study was aimed at verifying the hypothesis that p66(Shc) deletion also protects from diabetic glomerulopathy by reducing oxidative stress. Streptozotocin-induced diabetic p66(Shc) knockout (KO) mice showed less marked changes in renal function and structure, as indicated by the significantly lower levels of proteinuria, albuminuria, glomerular sclerosis index, and glomerular and mesangial areas. Glomerular content of fibronectin and collagen IV was also lower in diabetic KO versus wild-type mice, whereas apoptosis was detected only in diabetic wild-type mice. Serum and renal tissue advanced glycation end products and plasma isoprostane 8-epi-prostaglandin F2alpha levels and activation of nuclear factor kappaB (NF-kappaB) were also lower in diabetic KO than in wild-type mice. Mesangial cells from KO mice grown under high-glucose conditions showed lower cell death rate, matrix production, ROS levels, and activation of NF-kappaB than those from wild-type mice. These data support a role for oxidative stress in the pathogenesis of diabetic glomerulopathy and indicate that p66(Shc) is involved in the molecular mechanism(s) underlying diabetes-induced oxidative stress and oxidant-dependent renal injury.
Advanced glycation end product receptors (AGERs) play distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging. Overexpression of AGER1 in murine mesangial cells (MCs) (MC-R1) inhibited AGE-induced MAPK1,2 phosphorylation and NF-κB activity and also increased AGE degradation. The mechanism of the inhibitory effects of AGER1, upstream of MAPK, was explored in MCs and HEK293 AGER1-expressing cells. AGE-induced Ras activation was found to be linked to Shc/Grb2 complex formation and Shc phosphorylation in MCs, responses that were markedly reduced in MC-R1 cells. AGE responses also included EGF receptor (EGFR) phosphorylation in MCs or HEK293 cells, but this link was blocked in both MC-R1 and HEK293-R1 cells. Coexpression of AGER1 and EGFR in HEK293 cells decreased AGE-mediated EGFR and p44/p42 phosphorylation but not EGF-induced p44/p42 activation. AGE, S100/calgranulin, or H2O2 promoted MAPK phosphorylation in EGFR⁺ cells in a manner that was inhibitable by an EGFR inhibitor, AG1478. Also, in AGER1 cells, AGE-induced H2O2 formation and AGE- or S100-induced p44/p42 phosphorylation were suppressed, and these effects were restored by R1 siRNA. These data confirm that R1 negatively regulates AGE-mediated oxidant stress-dependent signaling via the EGFR and Shc/Grb2/Ras pathway. AGER1 could serve as a model for developing therapeutic targets against vascular and kidney disorders related to diabetes and aging.
• phosphorylation
• reactive oxygen species
• mesangial cells
• MAPK
• diabetes
Oxidative stress (OS) and inflammatory mediators increase with aging. The levels of advanced glycation endproducts (AGEs), prooxidant factors linked to chronic diseases such as diabetes, cardiovascular disease, and renal disease, also increase with aging. AGEs are readily derived from heat-treated foods. We propose that the excess consumption of certain AGEs via the diet enhances OS and inflammatory responses in healthy adults, especially in elderly persons.
We examined 172 young (<45 years old) and older (>60 years old) healthy individuals to determine whether the concentration of specific serum AGEs (N(epsilon)-carboxymethyl-lysine [CML] or methylglyoxal [MG] derivatives) were higher in older compared to younger persons and whether, independent of age, they correlated with the intake of dietary AGEs, as well as with circulating markers of OS and inflammation.
Body weight, body mass index (BMI), and serum AGE, CML, and MG derivatives were higher in older participants, independent of gender. Serum CML correlated with levels of 8-isoprostanes (r = 0.448, p =.0001) as well as with Homeostasis Model Assessment index (HOMA), an index of insulin resistance (r = 0.247, p =.044). The consumption of dietary AGEs, but not of calories, correlated independently with circulating AGEs (CML: r = 0.415, p =.0001 and MG: r = 0.282, p =.002) as well as with high sensitivity C-reactive protein (hsCRP) (r = 0.200, p =.042).
Circulating indicators of AGEs (CML and MG derivatives), although elevated in older participants, correlate with indicators of inflammation and OS across all ages. Indicators of both AGEs and OS are directly influenced by the intake of dietary AGEs, independent of age or energy intake. Thus, reduced consumption of these oxidants may prove a safe economic policy to prevent age-related diseases, especially in an aging population.
Advanced glycation end products (AGEs) promote reactive oxygen species (ROS) formation and oxidant stress (OS) in diabetes and aging-related diseases. AGE-induced OS is suppressed by AGER1, an AGE-receptor that counteracts receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR)-mediated Shc/Ras signal activation, resulting in decreased OS. Akt, FKHRL1, and antioxidants; e.g., MnSOD, regulate OS. Serine phosphorylation of p66(shc) also promotes OS. We examined the effects of two defined AGEs N(epsilon)-carboxy-methyl-lysine (CML) and methyl-glyoxal derivatives (MG) on these cellular pathways and their functional relationship to AGER1 in human embryonic kidney cells (HEK293). Stimulation of HEK293 cells with either AGE compound increased phosphorylation of Akt and FKHRL1 by approximately threefold in a redox-dependent manner. The use of p66(shc) mutants showed that the AGE-induced effects required Ser-36 phosphorylation of p66(shc). AGE-induced phosphorylation of FKHRL1 led to a 70% downregulation of MnSOD, an effect partially blocked by a phosphatidylinositol 3-kinase inhibitor (LY-294002) and strongly inhibited by an antioxidant (N-acetylcysteine). These pro-oxidant responses were suppressed in AGER1 overexpressing cells and reappeared when AGER1 expression was reduced by small interfering RNA (siRNA). These studies point to a new pathway for the induction of OS by AGEs involving FKHRL1 inactivation and MnSOD suppression via Ser-36 phosphorylation of p66(shc) in human kidney cells. This represents a key mechanism by which AGER1 maintains cellular resistance against OS. Thus the decrease of AGER1 noted in aging and diabetes may further enhance OS and reduce innate antioxidant defenses.
We tested the theory that reactive oxygen species cause aging. We augmented the natural antioxidant systems of Caenorhabditis elegans with small synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type worms increased their mean life-span by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their life-span (a 67 percent increase). It appears that oxidative stress is a major determinant of life-span and that it can be counteracted by pharmacological intervention.
We tested the theory that reactive oxygen species cause aging. We augmented the natural antioxidant systems ofCaenorhabditis elegans with small synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type worms increased their mean life-span
by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their life-span (a 67 percent
increase). It appears that oxidative stress is a major determinant of life-span and that it can be counteracted by pharmacological
intervention.
alpha -Dicarbonyl compounds are of major interest in food chemistry and biochemistry as important precursors of, for example, protein modifications and flavor. Due to their high reactivity most of the published structures were identified and quantitated as stable derivatives after reaction with trapping reagents. However, the present study showed for the first time that the trapping reagents are of dramatic impact on the final qualitative and quantitative alpha -dicarbonyl spectrum. As important representatives, aminoguanidine and o-phenylenediamine were used to compare trapping characteristics and to monitor the dicarbonyl structures arising from the degradation of an Amadori compound. Dicarbonyl structures with a reductone moiety could not be or were only insufficiently detected by slow-reacting reagents such as aminoguanidine. On the other hand, fast-reacting chemicals such as o-phenylenediamine imposed high oxidative stress on the investigated system and led to enhanced or false positive formation of dicarbonyl compounds generated by oxidative pathways.
Caloric restriction (CR), the consumption of fewer calories without malnutrition, and reduced insulin and/or IGFI receptor signaling delay many age-related physiological changes and extend the lifespan of many model organisms. Here, we present and review microarray and biochemical studies indicating that the potent anticancer effects of CR and disrupted insulin/IGFI receptor signaling evolved as a byproduct of the role of many mitotic tissues as reservoirs of metabolic energy. We argue that the longevity effects of CR are derived from repeated cycles of apoptosis and autophagic cell death in mitotically competent tissues and protein turnover and cellular repair in postmitotic tissues. We review studies showing that CR initiated late in life can rapidly induce many of the benefits of lifelong CR, including its anticancer effects. We also discuss evidence from liver and heart indicating that many benefits of lifelong CR are recapitulated in mitotic and postmitotic tissues when CR is initiated late in life.
A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Such modifications
mark enzymes for degradation by cytosolic neutral alkaline proteases. Protein oxidation contributes to the pool of damaged
enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized
protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations
or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein.
To determine the effects of age on the myocardium, the functional and structural characteristics of the heart were studied in rats at 4, 12, 20, and 29 months of age. Mean arterial pressure, left ventricular pressure and its first derivative (dP/dt), and heart rate were comparable in rat groups up to 20 months. During the interval from 20 to 29 months, elevated left ventricular end-diastolic pressure and decreased dP/dt indicated that a significant impairment of ventricular function occurred with senescence. In the period between 4 and 12 months, a reduction of nearly 19% in the total number of myocytes was measured in both ventricles. In the subsequent ages, similar decreases in myocyte cell number were found in the left ventricle, whereas in the right ventricle, the initial loss was fully reversed by 20 months. Moreover, from 20 to 29 months, a 59% increase in the aggregate number of myocytes occurred in the right ventricular myocardium. In the left ventricle, a 3% increment was also seen, but this small change was not statistically significant. These estimations of myocyte cellular hyperplasia, however, were complicated by the fact that cell loss continued to take place with age. The volume fraction of collagen in the tissue, in fact, progressively increased from 8% and 7% at 4 months to 16% and 22% at 29 months in the left and right ventricles, respectively. In conclusion, myocyte cellular hyperplasia tends to regenerate the ventricular mass being lost with age in the adult mammalian rat heart.
Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry. Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes. We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference.
Tissue content of advanced glycation end products (AGE) increases with age and contributes to the changes in structure and function of the renal and cardiovascular systems. The effect of chronic food restriction on this AGE accumulation was investigated in lean WAG/Rij rats. A 30% food restriction performed from 10 to 30 mo in female rats reduced their mean body weight from 240 +/- 7 to 160 +/- 12 g, but did not modify their survival. AGE collagen content increased from 14.3 +/- 5.5 to 104.7 +/- 13.0 arbitrary units per microgram (AU/microg) of hydroxyproline (OHPro) in kidney between 10 and 30 mo, and from 9.7 +/- 1.2 to 310.6 +/- 34.6 AU/microg OHPro in the abdominal aorta. Food restriction reduced AGE accumulation to 21.4 +/- 3.3 and 74.6 +/- 16.5 AU/microg OHPro in kidney and aorta of 30-mo-old animals. Similar results were found for collagen prepared from isolated glomeruli (7.8 +/- 1.2, 81.2 +/- 16.1, and 10.3 +/- 4.3 AU/microg OHPro in 10-mo, 30-mo, and restricted 30-mo-old rats). Reduction of intrarenal and arterial AGE accumulation by food restriction was confirmed by immunostaining in optical microscopy. Age-related changes in arterial and kidney structures as polyuria and proteinuria were mainly prevented by food restriction. These data indicate that chronic food restriction reduces the accumulation of AGE and preserves the structure and function of the renal and cardiovascular systems in learn rats, although it did not affect survival of the animals between 10 and 30 mo.
alpha-Dicarbonyl compounds are of major interest in food chemistry and biochemistry as important precursors of, for example, protein modifications and flavor. Due to their high reactivity most of the published structures were identified and quantitated as stable derivatives after reaction with trapping reagents. However, the present study showed for the first time that the trapping reagents are of dramatic impact on the final qualitative and quantitative alpha-dicarbonyl spectrum. As important representatives, aminoguanidine and o-phenylenediamine were used to compare trapping characteristics and to monitor the dicarbonyl structures arising from the degradation of an Amadori compound. Dicarbonyl structures with a reductone moiety could not be or were only insufficiently detected by slow-reacting reagents such as aminoguanidine. On the other hand, fast-reacting chemicals such as o-phenylenediamine imposed high oxidative stress on the investigated system and led to enhanced or false positive formation of dicarbonyl compounds generated by oxidative pathways.
Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegansand the p66shc locus in mice. We demonstrate thatp66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity.
In p66shc
–/– cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced.
In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance.
These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins,
p66shc, and intracellular oxidants.
Reactive advanced glycation end products (AGEs), known to promote diabetic tissue damage, occur endogenously as well as in heated foods and are orally absorbed. The relative contribution of diet-derived AGEs to diabetic nephropathy (DN) remains unclear.
We tested a standard mouse food (AIN-93G) found to be rich in AGEs (H-AGE diet) in parallel with a similar diet that contained six-fold lower AGE content (L-AGE), but equal calories, macronutrients, and micronutrients. Non-obese diabetic mice (NOD) with type 1 diabetes (T1D) and db/db mice with type 2 diabetes (T2D) were randomly assigned to each formula for either 4 or 11 months, during which time renal parameters and AGE levels were assessed.
Compared to the progressive DN and short survival seen in NOD mice exposed to long-term H-AGE feeding, L-AGE-fed NOD mice developed minimal glomerular pathology and a modest increase in urinary albumin:creatinine ratio (p<0.005), and a significantly extended survival (p<0.0001), consistent with lower serum (p<0.025) and kidney AGEs (p<0.01). Also, in the 4-month study, and in contrast to the H-AGE-fed mice, L-AGE-fed NOD and db/db mice exhibited low levels of renal cortex TGF beta-1 (p<0.05), laminin B1 mRNA (p<0.01) and alpha 1 IV collagen mRNA (p<0.05) and protein, in concert with reduced serum and kidney AGEs (p<0.05, respectively).
Intake of high-level, food-derived AGEs is a major contributor to DN in T1D and T2D mice. Avoidance of dietary AGEs provides sustained protection against DN in mice; providing the rationale for similar studies in human diabetic patients.
Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-alphabeta-actin mRNA ratio was 1.4 +/- 0.5 on H-AGE and 0.9 +/- 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 +/- 429 and 698 +/- 347 ngml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-alpha rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.
Advanced glycation endproduct (AGE) levels are elevated in renal failure patients and may contribute to the excessive cardiovascular disease in this population. Diet-derived AGE are major contributors to the total body AGE pool. It was postulated that a reduction in dietary AGE intake might impact on the high circulating AGE levels in renal failure patients. Twenty-six nondiabetic renal failure patients on maintenance peritoneal dialysis were randomized to either a high or a low AGE diet for 4 wk. Three-day dietary records, fasting blood, 24-h urine, and dialysis fluid collections were obtained at baseline and end of study. AGE levels were determined by ELISA for N(epsilon)-carboxymethyl-lysine (CML) and methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low dietary AGE intake decreased serum CML (34%; P < 0.002), serum MG (35%; P < 0.008), CML-LDL (28%; P < 0.011), CML-apoB (25%; P < 0.028), dialysate CML (39%; P < 0.03), and dialysate MG output (40%; P < 0.04). High dietary AGE intake increased serum CML (29%; P < 0.028), serum MG (26%; P < 0.09), CML-LDL (50%; P < 0.011), CML-apoB (67%; P < 0.028), and dialysate CML output (27%; P < 0.01). Serum AGE correlated with BUN (r = 0.6, P < 0.002 for CML; r = 0.4, P < 0.05 for MG), serum creatinine (r = 0.76, P < 0.05 for CML; r = 0.55, P < 0.004 for MG), total protein (r = 0.4, P < 0.05 for CML; r = 0.4, P < 0.05 for MG), albumin (r = 0.4, P < 0.02 for CML; r = 0.4, P < 0.05 for MG), and phosphorus (r = 0.5, P < 0.006 for CML; r = 0.5, P < 0.01 for MG). It is concluded that dietary glycotoxins contribute significantly to the elevated AGE levels in renal failure patients. Moreover, dietary restriction of AGE is an effective and feasible method to reduce excess toxic AGE and possibly cardiovascular associated mortality.
Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.
Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.
Organisms are constantly exposed to many different forms of reactive oxygen species and reactive nitrogen species that damage proteins, nucleic acids, and lipids, leading to loss of biological function. The possibility that reactive oxygen/nitrogen-mediated protein damage contributes to the aging process is supported by results of many studies showing that aging is associated with the accumulation of such protein damage. Summarized here are results of studies, showing that the accumulation of,protein damage is a complex function of a multiplicity of factors that govern the intracellular levels of reactive oxygen/nitrogen species, on the one hand, and a multiplicity of factors that govern the degradation and/or repair of damaged proteins, on the other. Basic mechanisms involved in the modification of proteins by various forms of reactive oxygen/nitrogen species are also discussed.
Several single gene mutations in mice that increase the murine life span have been identified, including the Pit-1 mutation which results in the Snell dwarf (Pit1(dw/dw)), however, the biological mechanism of this life-span extension is still unclear. Based on studies that show oxidative stress plays an important role in the aging process, we hypothesized that the increased longevity seen in Snell dwarf mice may result from a resistance to oxidative stress. We report that Snell dwarf mice respond to oxidative stress induced by 3-NPA differently than their wild type littermates. This altered response results in diminished activation of the MEK-ERK kinase cascade and virtually no phosphorylation of c-Jun at Ser63 in dwarf mice after 3-NPA treatment, despite a robust phosphorylation of Ser63 in wild type mice. We propose that this altered management of oxidative stress in dwarf mice is partially responsible for the increased longevity in Snell dwarf mice.
Advanced glycoxidation end products (AGEs), the derivatives of glucose-protein or glucose-lipid interactions, are implicated in the complications of diabetes and aging. The objective of this article was to determine the AGE content of commonly consumed foods and to evaluate the effects of various methods of food preparation on AGE production.
Two-hundred fifty foods were tested for their content in a common AGE marker (epsilon)N-carboxymethyllysine (CML), using an enzyme-linked immunosorbent assay based on an anti-CML monoclonal antibody. Lipid and protein AGEs were represented in units of AGEs per gram of food.
Foods of the fat group showed the highest amount of AGE content with a mean of 100+/-19 kU/g. High values were also observed for the meat and meat-substitute group, 43+/-7 kU/g. The carbohydrate group contained the lowest values of AGEs, 3.4+/-1.8 kU/g. The amount of AGEs present in all food categories was related to cooking temperature, length of cooking time, and presence of moisture. Broiling (225 degrees C) and frying (177 degrees C) resulted in the highest levels of AGEs, followed by roasting (177 degrees C) and boiling (100 degrees C).
The results indicate that diet can be a significant environmental source of AGEs, which may constitute a chronic risk factor for cardiovascular and kidney damage.
Glyoxal is a reactive alpha-oxoaldehyde that is a physiological metabolite formed by lipid peroxidation, ascorbate autoxidation, oxidative degradation of glucose and degradation of glycated proteins. Glyoxal is capable of inducing cellular damage, like methylglyoxal (MG), but may also accelerate the rate of glycation leading to the formation of advanced glycation end-products (AGEs). However, the mechanism of glyoxal cytotoxicity has not been precisely defined. In this study we have focused on the cytotoxic effects of glyoxal and its ability to overcome cellular resistance to oxidative stress. Isolated rat hepatocytes were incubated with different concentrations of glyoxal. Glyoxal by itself was cytotoxic at 5mM, depleted GSH, formed reactive oxygen species (ROS) and collapsed the mitochondrial membrane potential. Glyoxal also induced lipid peroxidation and formaldehyde formation. Glycolytic substrates, e.g. fructose, sorbitol and xylitol inhibited glyoxal-induced cytotoxicity and prevented the decrease in mitochondrial membrane potential suggesting that mitochondrial toxicity contributed to the cytotoxic mechanism. Glyoxal cytotoxicity was prevented by the glyoxal traps d-penicillamine or aminoguanidine or ROS scavengers were also cytoprotective even when added some time after glyoxal suggesting that oxidative stress contributed to the glyoxal cytotoxic mechanism.
The Free Radical/Oxidative Stress Theory of Aging, which was first proposed in 1956, is currently one of the most popular explanations for how aging occurs at the biochemical/molecular level. However, most of the evidence in support of this theory is correlative, e.g., oxidative damage to various biomolecules increases with age, and caloric restriction, which increases life span and retards aging, reduces the age-related increase in oxidative damage to biomolecules. The most direct test of the Free Radical/Oxidative Stress Theory of Aging is to specifically alter the age-related increase in oxidative damage and determine how this alteration affects life span. For the first time, investigators can use genetically altered animals to test directly the role of oxidative damage in aging. In this manuscript, we critically review the past research in this area and discuss potential future research directions in testing the Free Radical/Oxidative Theory of Aging.
Intermittent fasting (IF; reduced meal frequency) and caloric restriction (CR) extend lifespan and increase resistance to age-related diseases in rodents and monkeys and improve the health of overweight humans. Both IF and CR enhance cardiovascular and brain functions and improve several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity. Cardiovascular stress adaptation is improved and heart rate variability is increased in rodents maintained on an IF or a CR diet. Moreover, rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke. The beneficial effects of IF and CR result from at least two mechanisms--reduced oxidative damage and increased cellular stress resistance. Recent findings suggest that some of the beneficial effects of IF on both the cardiovascular system and the brain are mediated by brain-derived neurotrophic factor signaling in the brain. Interestingly, cellular and molecular effects of IF and CR on the cardiovascular system and the brain are similar to those of regular physical exercise, suggesting shared mechanisms. A better understanding of the cellular and molecular mechanisms by which IF and CR affect the blood vessels and heart and brain cells will likely lead to novel preventative and therapeutic strategies for extending health span.
The interaction of advanced glycation end products (AGEs) with their main receptor RAGE in endothelial cells induces intracellular generation of reactive oxygen species (ROS) and the expression of vascular cell adhesion molecule (VCAM)-1. We investigated the role of distinct sources of ROS, including the mitochondrial electron transport chain, NAD(P)H oxidase, xanthine oxidase, and arachidonic acid metabolism, in AGE-induced VCAM-1 expression.
The induction of ROS and VCAM-1 by AGEs in cultured human umbilical vein endothelial cells was specifically blocked by an anti-RAGE antibody. The inhibition of NAD(P)H oxidase by apocynin and diphenylene iodonium, and of the mitochondrial electron transport system at complex II by thenoyltrifluoroacetone (TTFA), significantly inhibited both AGE-induced ROS production and VCAM-1 expression, whereas these effects were potentiated by rotenone and antimycin A, specific inhibitors of mitochondrial complex I and III, respectively. The inhibition of Cu/Zn superoxide dismutase inhibited both ROS and VCAM-1 induction, indicating that H2O2 by this source is involved as a mediator of VCAM-1 expression by AGEs.
Altogether, these results demonstrate that ROS generated by both NAD(P)H-oxidase and the mitochondrial electron transport system are involved in AGE signaling through RAGE, and indicate potential targets for the inhibition of the atherogenic signals triggered by AGE-RAGE interaction.
It has been known for some 70 years that restricting the food intake of laboratory rats extends their mean and maximum life span. In addition, such life extension has been observed over the years in many other species, including mice, hamsters, dogs, fish, invertebrate animals, and yeast. Since this life-extending action appears to be due to a restricted intake of energy, this dietary manipulation is referred to as caloric restriction (CR). CR extends life by slowing and/or delaying the ageing processes. The underlying biological mechanism responsible for the life extension is still not known, although many hypotheses have been proposed. The Growth Retardation Hypothesis, the first proposed, has been tested and found wanting. Although there is strong evidence against the Reduction of Body Fat Hypothesis, efforts have recently been made to resurrect it. While the Reduction of Metabolic Rate Hypothesis is not supported by experimental findings, it nevertheless still has advocates. Currently, the most popular concept is the Oxidative Damage Attenuation Hypothesis; the results of several studies provide support for this hypothesis, while those of other studies do not. The Altered Glucose-Insulin System Hypothesis and the Alteration of the Growth Hormone-IGF-1 Axis Hypothesis have been gaining favor, and data have emerged that link these two hypotheses as one. Thus, it may now be more appropriate to refer to them as the Attenuation of Insulin-Like Signaling Hypothesis. Finally, the Hormesis Hypothesis may provide an overarching concept that embraces several of the other hypotheses as merely specific examples of hormetic processes. For example, the Oxidative Damage Attenuation Hypothesis probably addresses only one of likely many damaging processes that underlie aging. It is proposed that low-intensity stressors, such as CR, activate ancient hormetic defense mechanisms in organisms ranging from yeast to mammals, defending them against a variety of adversities and, when long-term, retarding senescent processes.
Organisms are constantly exposed to various forms of reactive oxygen species (ROS) that lead to oxidation of proteins, nucleic acids, and lipids. Protein oxidation can involve cleavage of the polypeptide chain, modification of amino acid side chains, and conversion of the protein to derivatives that are highly sensitive to proteolytic degradation. Unlike other types of modification (except cysteine oxidation), oxidation of methionine residues to methionine sulfoxide is reversible; thus, cyclic oxidation and reduction of methionine residues leads to consumption of ROS and thereby increases the resistance of proteins to oxidation. The importance of protein oxidation in aging is supported by the observation that levels of oxidized proteins increase with animal age. The age-related accumulation of oxidized proteins may reflect age-related increases in rates of ROS generation, decreases in antioxidant activities, or losses in the capacity to degrade oxidized proteins.
Insulin resistance is a key feature of type 2 diabetes. It is also involved in the development and progression of microvascular complications. We analysed the relationship between parental history of diabetes, insulin resistance and diabetic nephropathy (DN) and assessed the specific maternal and paternal influences of history of type 2 diabetes on DN in type 1 diabetic offspring.
We recorded information regarding family history of type 2 diabetes and of cardiovascular disease in 160 consecutive, unrelated type 1 diabetic patients. Insulin resistance was assessed using a validated estimation of the glucose disposal rate (eGDR).
Type 1 diabetic patients with a maternal history of type 2 diabetes were more likely to be insulin-resistant (P=0.043) and to have renal complications (P=0.0041) than those from the reference group (without parental history of diabetes), while patients with a paternal history were not different from those from the reference group, regarding eGDR and DN. Time to development of abnormal albuminuria was significantly affected by maternal history of type 2 diabetes (log-rank=12.66; P=0.0004) and by familial history of premature cardiovascular disease (log-rank=5.48; P=0.0234). In multivariate analysis, a maternal history of type 2 diabetes was independently associated with nephropathy after adjustment for sex, diabetes duration and familial history of premature cardiovascular disease.
Maternal history of type 2 diabetes is independently associated with DN in type 1 diabetic patients. This might suggest the transmission of a maternal trait related to microvascular complications, raising the hypothesis of imprinted genes predisposing to diabetic renal disease.
Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.