DOI 10.1515/hmbci-2013-0031      Horm Mol Biol Clin Invest 2013; 16(2): 55–64

Volkan Ergin, Elif Burcu Bali, Reza Ebrahimi Hariry and Çimen Karasu*

Natural products and the aging process Abstract: Literature surveys show that the most of the research that have been conducted on the effect of herbal remedies on many tissue pathologies, including metabolic disturbances, cardiovascular decline, neurodegeneration, cataract, diabetic retinopathy and skin inflammation, all lead to an accelerated aging process. The increased carbonylation of proteins (carbonyl stress) disturbing their function has been indicated as an underlying mechanism of cellular senescence and age-related diseases. Because it is also linked to the carbonyl stress, aging chronic disease and inflammation plays an important role in understanding the clinical implications of cellular stress response and relevant markers. Greater knowledge of the molecular and cellular mechanisms involved in several pathologies associated with aging would provide a better understanding to help us to develop suitable strategies, use specific targets to mitigate the effect of human aging, prevent particularly chronic degenerative diseases and improve quality of life. However, research is lacking on the herbal compounds affecting cellular aging signaling as well as studies regarding the action mechanism(s) of natural products in prevention of the age-related disease. This review provides leads for identifying new medicinal agents or potential phytochemical drugs from plant sources for the prevention or delaying cellular aging processes and the treatment of some disorders related with accelerated body aging. Keywords: age-related diseases; body aging; carbonyl stress; cellular stress; herbal phenolics; herbal remedies; nutraceuticals; phytochemicals; protein oxidation; senescense. *Corresponding author: Prof. Dr. Çimen Karasu, Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler 06500, Ankara, Turkey, E-mail: [email protected]; [email protected] Volkan Ergin: Faculty of Medicine, Department of Medical Biology and Genetics, Gazi University, Ankara, Turkey Elif Burcu Bali: Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Ankara, Turkey; and FARMASENS Biotech Co., Gazi University Technopark, Ankara, Turkey Reza Ebrahimi Hariry: Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Ankara, Turkey

Introduction It has been proposed that cells change as a function of aging and that such changes may reflect a diminished capability for the cells to perform their normal function [1]. To maintain homeostasis, the cells are required to rapidly respond in a manner that will allow for clearance of aberrant proteins, invading pathogens, damaged tissue debris and remodeling. Any deficit in the ability of the cells to perform these functions, whether because of a decrease in cell number or diminished function, would have a significant impact on the health of the tissues. For instance, it has been reported that changes in the aging microglia drive pathogenic progression of diseases or injury through a diminution of neuroprotective functions, increase in neurotoxicity, and dysregulation of responses to signals and perturbations [2]. Microglial cells show cytoplasmic inclusions, de-ramification of processes, and membrane blebbing with aging. Age-related changes in cytokine production and dysmorphic microglia morphology have been proposed to underlie microglia contributions to neurodegenerative diseases [3]. Aging is a condition that favors the development of many degenerative diseases, such as atherosclerosis, Alzheimer’s disease, heart attacks, skin wrinkles, macular degeneration and chronic metabolic diseases which have been associated with a breakdown in repair processes that occur in response to cell damage interventions. Agespecific mortality rates from cardiovascular diseases and strokes increase with age throughout the later years of life. Evidence has demonstrated that in the absence of other risk factors, aging per se causes the development of athero­ sclerosis [4]. Aging has been considered as an independent factor associated with endothelial dysfunction even in the absence of other cardiovascular risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking or a sedentary lifestyle, as well as genetic factors [5]. Conversely, age-associated morbidity of ocular diseases, including macular degeneration, diabetic retinopathy, and dry eye disease, has been gradually increasing worldwide [6]. Skin aging is a complex biological process influenced by a combination of endogenous or intrinsic and exogenous or extrinsic factors. Because of the fact that skin health and beauty is considered one of the principal factors representing overall “well-being”

56      Ergin et al.: Natural products against aging and the perception of “health” in humans, several antiaging strategies have been developed during recent years [7]. Many hormone levels, such as dehydroepiandrosterone, fall with age in men and women, sometimes reaching values as low as 10%–20% of those encountered in young individuals. This age-related decrease suggests an “adrenopause” phenomenon [8]. Similarly, the secretion of growth hormone, and consequently that of insulin-like growth factor 1, declines over time until only low levels can be detected in individuals aged   ≥  60 years [9]. In addition, recent studies indicated that aging, while reducing sensitivity to ghrelin-mediated increases in body weight gain and food intake, might enhance the responsiveness to the stimulatory effects of ghrelin on lipid metabolites and hypothalamic-pituitary-adrenal axis activity [10]. Understanding the molecular mechanisms underlying the aging process may provide the best strategy for addressing the challenges assumed by aging populations worldwide. The dysregulation of the biological systems associated with aging are generated partly through damage in cellular signaling molecules that accumulates over time. One major source of this injury is redox stress, which can impair biological structures and the mechanisms by which they are repaired. In this sense, there must be a balance between the rate of cellular damage and renewal to maintain homeostasis and tissue function. Reactive oxygen species (ROS) are generated constantly within cells at low concentrations even under physiological conditions. Fifty  years ago, Harman et  al. suggested that aging might be mediated by macromolecular damage through reactions involving ROS [11]. Today, a version of the free radical theory of aging, focusing on mitochondria as source as well as the target of ROS, is one of the most popular theories of aging. During aging the levels of ROS can increase because of a limited capacity of antioxidant systems and repair mechanisms [12]. Proteins are among the main targets for oxidants because of their high rate constants for several reactions with ROS and their abundance in biological systems. Protein damage has an important effect on cellular viability as most protein damage is nonrepairable, and has deleterious consequences on protein structure and function. In addition, damaged and modified proteins can form cross-links and provide a basis for many senescence-associated alterations and may contribute to a range of human pathologies [13]. The degrading systems as proteolytic systems and the lysosomal system provide a last line of antioxidative protection, removing irreversibly damaged proteins and recycling amino acids for the continuous protein synthesis. It is now well known that during aging both systems are affected and their proteolytic activity declines significantly [13, 14]. In addition,

aging, inflammation and oxidative stress are endogenous factors that cause telomere shortening, which is dependent on oxidative cell damage. It has been demonstrated that microglia exhibits telomere shortenings and decreased telomerase activity with aging [15] and in Alzheimer’s disease brains [16], supporting the hypothesis of microglial replicative senescence in normal and pathological aging. While a classic outcome of cell senescence is a diminished proliferative ability, it is likely that a more general blunting of functional activities occurs. However, age-related cellular degeneration might not only be caused by loss of cell functional properties, but also by the actual loss of the cells as in the case of Alzheimer’s disease [17]. Thus, pathologies associated with aging and age may be caused by the long-term effects of redox damage, which are modified by genetic and environmental factors. Here we highlight the recent advances in the understanding of cellular response to increased protein oxidation and the prevention strategies of protein damage by natural products during aging.

Response to carbonyl stress: impaired cellular redox homeostasis in aging signaling and diseases processes In biological systems, the redox potential of the intracellular compartment dictates whether a particular reaction can or cannot occur. Redox biochemistry influences most of the cellular processes and has been shown to underpin aging and many human diseases. Integrating the complexity of redox signaling and regulation is perhaps one of the most challenging areas of biology [18]. Protein oxidative modifications, also known as protein oxidation, are a major class of protein post-translational modifications. They are caused by reactions between protein amino acid residues and ROS or reactive nitrogen species (RNS) and can be classified into two categories: irreversible modifications and reversible modifications. Protein oxidation has been often associated with functional decline of the target proteins, which are thought to contribute to normal aging and age-related pathogenesis [13, 19]. It has now been recognized, however, that protein oxidation can also play a positive role in many cellular functions. This gradual realization of the beneficial roles of protein oxidation may be attributed to accumulating evidence that ROS and RNS are indispensible for cell survival and regeneration, and in many cases, they are required for recovery of cellular

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functions by creating positive stress conditions whereby cell survival mechanisms are reprogramed to extend life span or to counteract severe, or lethal challenges [19–21]. Apparently, the adaptation to the increased oxidant or reductant status is important to cell survival and the cellular redox homeostasis is essential to maintain a normal long life. Reactions between sugars and free amino groups on proteins and lipids are an inevitable consequence of aldehyde reactivity, begin with the formation of Schiff bases and ε-amino groups that rearrange to Amadori adducts and other reactive carbonyl compounds (RCCs). These intermediates can undergo further oxidation and dehydration reactions to form irreversible protein-bound compounds, collectively termed ‘advanced glycation end products’ (AGEs) [22–24]. Glyco-oxidation is a term used for glycation processes involving oxidation. It has been demonstrated that aging-related decline in myofibrillar protein function is affected by a number of structural and functional modifications, including glyco-oxidation [25]. It is important to appreciate that proteins can also be modi­fied by lipids as well as carbohydrates. During oxidative stress, ROS attack polyunsaturated fatty acids (PUFAs) either in the cell membrane or circulating lipoprotein molecules. This oxidative decomposition of PUFAs initiates chain reactions that lead to the formation of a variety of reactive carbonyl species. Among them is 4-hydroxytrans-2-nonenal (4-HNE), which subsequently reacts via the ‘Michael addition’ mechanism with cysteine, histidine and lysine residues in proteins, generating relatively stable adducts known as ‘advanced lipid peroxidation end products’ (advanced lipo-oxidation end products ALEs) [22, 23, 26]. RCCs may induce ‘carbonyl stress’ characterized by the increased formation of adducts and cross-links on proteins. A growing body of evidence demonstrates that carbonyl stress associates the promotion of cytotoxic events such as cell growth arrest, mitochondrial dysfunction, apoptosis, and necrosis by modifying cellular proteins and nucleic acids, contributing to the dysfunction and damages in tissues and to the progression of diseases [22, 23, 27–29]. Carbonyl stress increases during aging and has been consistently associated with many pathologies such as diabetes, atherosclerosis, cataracts, Alzheimer’s disease, and more [27, 29, 30]. As protein carbonyls are the most commonly used markers of protein oxidation, new methods have been developed for the detection and quantification of carbonylated proteins. Proteomics approaches, i.e., fluorescent-based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent

of protein oxidative and related modifications and for identifying the targeted proteins [31]. The identification of these protein targets is of valuable interest in order to understand the mechanisms by which damaged proteins accumulate and potentially affect cellular functions during oxidative stress, cellular senescence and/or aging in vivo. Serum AGEs [N(epsilon)-carboxymethyl-lysine (CML) or methylglyoxal (MG) derivatives] have been found to be higher in older compared to younger subjects [32]. The results obtained from the mimetic aging model rats shows that various anatomical regions of the brain have different susceptibility to oxidative damage of proteins, lipids and DNA [33, 34]. In addition to the brain, there are many studies that report increased advanced oxidative and glyco-oxidative protein damage markers in kidney [35, 36], heart [27, 34, 37], pancreas [38], aorta [39, 40], liver [41] and serum [42] by aging or accelerated aging models such as diabetes. Advanced oxidation protein products represent dityrosine-containing cross-linked protein modifications formed mainly via myeloperoxidase reaction, and have been demonstrated to accelerate the uremiaassociated atherogenesis and renal fibrosis in children and adolescents [43]. Increased ‘nitroxidative stress’ causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins, and the persistent mitochondrial dysfunction has been suggested to contribute to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease [44]. It has been reported that the increased level of serum or tissue AGEs is a risk factor for the production of colorectal cancer [45] and impairment of cognitive and memory functions [46, 47] associated with insulin resistance [48] and promote diabetic complications [49]. Some authors propose that the excessive consumption of certain AGEs via the diet enhances redox stress and inflammatory responses in healthy adults, especially in elderly persons [32]. There are also atherosclerotic risk markers in prediabetic and diabetic elderly subjects [42], markers for ocular complications in vitro and in vivo models of human age-related eye diseases, such as cataracts [50]. Blockade of ROS-dependent signaling pathways or disruptions of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in pulmonary hypertension [51]. In physiological levels, ROS are seen as being involved in cellular regulation by acting as redox signals, and their harmful effects are seen mostly as a result of compromised signaling, rather than caused by direct damage to sensitive targets. According to this view, ROS such as hydrogen peroxide and superoxide are not just causative agents of aging but may also be agents that increase the

58      Ergin et al.: Natural products against aging lifespan by acting, for example, as prosurvival signals [19, 52]. Indeed, ROS have crucial roles in redox regulation of protein phosphorylation, ion channels, and transcription factors. ROS are also required for biosynthetic processes, including thyroid hormone production, crosslinking of theextracellular matrix [53] and insulin release from pancreatic beta-cells [54, 55]. In pancreatic β-cells, evidence is emerging that acute and transient glucosedependent H2O2 contributes to normal glucose-stimulated insulin secretion. However, chronic and persistent elevation of H2O2, resulting from inflammation or excessive metabolic fuels such as glucose and fatty acids, may elevate antioxidant enzymes such that they blunt H2O2induced physiologically redox signaling, thus impairing β-cell function [54–57]. Similarly, it has been very recently reported by Vina et  al. that reductive stress in young healthy individuals at risk of Alzheimer disease implicates the importance of cellular redox homeostasis for health span extension [58]. In association with this, the balance between the oxidized [NAD(+)] and the reduced (NADH) forms of nicotinamide adenine dinucleotidesis critical for the cell’s proper function and ultimately, for its survival. It is expected that alterations to the NAD(+)/NADH ratio are to be found in cases of metabolic diseases, for example diabetes, due to the necessary cofactor of NAD(+) for several enzymes’ activity, many of which are related to metabolism. A decrease in the NAD(+)/NADH ratio causes these enzymes to decrease in activity (reductive stress), resulting in an altered metabolic situation that has been suggested recently as the first step toward several pathologies, such as diabetes [59].

The natural regulators of cellular redox homeostasis and protein oxidation In fact, ROS-related disease can be either caused by a lack of ROS (e.g., chronic granulomatous disease or certain autoimmune disorders) or a surplus of ROS (e.g., the gene­ ration of diabetes or cardiovascular and neurodegenerative complications of diabetes). Accumulation of damaged macromolecules, including oxidatively damaged (carbonylated) proteins, is a hallmark of cellular and organismal aging and age-related diseases. Thus understanding the molecular and cellular mechanisms that underlie the aging process would provide a good strategy to address the problems presented by the aging of the world’s population. Considering that in micronutrients, phyto-chemicals

are a very important source of redox regulators, in this review we are analyzing the relationship between cellular redox regulators and the aging mechanisms that may be involved in a higher survival rate and a lower incidence of the diseases associated with aging in populations that follow a healthy diet. Recent studies show that several natural extracts/ compounds such as polyphenolic-rich extracts serve as cellular redox regulator and can prevent the formation or accumulation of AGEs [60–63]. A new approach that is feasible nowadays involves drug targeting for specific pathways that control oxidative, inflammatory and ‘proteotoxic stress’. In this new scenario, the transcription factor Nrf2, master regulator of redox homeostasis, takes a central stage. Aged garlic extract, which is an odorless garlic preparation containing S-allylcysteine, has been reported to activate Nrf2 factor in the cerebral cortex [64]. A herbal chemopreventive agent, oridonin, represents a novel class of Nrf2 activator, and has an enhancing effect on cellular redox capacity, reduces formation of ROS, and improves the survival of cells after metal exposure [65]. In hyperglycemic and oxidative conditions, broccoli and sprouts have the potential to activate the Nrf2-dependent antioxidant response signaling pathway and attenuate oxidative stress, and inactivate the key modulators of inflammatory pathways as nuclear factor-kappaB (NF-κB) [66]. Interestingly, sulforaphane, the active compound of both vegatables, induces some peroxisome proliferator-activated receptors, which contribute to the regulation of lipid metabolism and glucose homeostasis [66]. In another example, fermented papaya preparation has been defined as a redox regulator in the blood cells of beta-thalassemic mice and patients [67]. Some plants compounds such as iridoids, glycosides and polyphenols ameliorate hyperglycemia, proteinuria and renal AGEs formation in the same way as with aminoguanidine [68]. Early experiments by our laboratory demonstrated the AGEs/ALEs inhibitory effect of that natural vitamin E in vivo [69]. The anthraquinones isolated from the seeds of Cassia tora are characterized as inhibitory against AGEs formation and rat lens aldose reductase [70], which leads to age- and diabetes-related ocular dysfunction [71]. The pomegranate (Punica granatum L.) hulk and seed extracts is the subject of our current research interest and demonstrated an aldose reductase and AGEs/ALEs inhibitor activity [72], and pomegranate extracts exhi­ bited a higher anti-AGE activity than hazelnut, almond and sesame extracts in protein-methylglyoxal assay [73]. Conversely, epigallocatechin-3-gallate has a direct trapping agent of RCCs that has been suggested to also

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contribute to the significant reduction of acrolein and other aldehydes in the peroxidation of seal blubber oil [74]. A similar study highlighted that an apple phenolic compound, phloretin, is a promising candidate in the prevention or treatment of acrolein-associated human diseases [75]. Phenolics are also important in the inhibition of cellular nitosative stress as demonstrated widely. For example, [6]-Gingerol, a pungent phenolic compound present in ginger, suppressed peroxynitriteinduced oxidation and 3-nitrotyrosine formation in bovine serum albumin [76]. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as systemic IL-6 level and hepatic IL-6 mRNA were markedly reduced in green tea extract-fed rats compared with controls after hemorrhage/resuscitation [77]. Conversely, phytotherapy has an important role in the management of diabetes induction, and functional foods and their nutraceutical components are now considered as supplementary treatments in type II diabetes and prevention of its long-term complications. In this respect, recent study showed that different fractions of Catharanthus roseus L. (Apocynaceae), Ocimum sanctum L. (Labiatae), Tinospora cordifolia Willd. (Menispermaceae), Aegle marmelos L. (Rutaceae), Ficus golmerata L. (Moraceae), Psoralea corlifolia L. (Fabaceae), Tribulus terrestris L. (Zygophyllaceae), and Morinda cetrifolia L. (Rubiaceae) have inhibitory activity on aldose reductase, a key enzyme implicated in cataractogenesis in diabetes [78]. In fact, the natural phenolic compounds with combined antioxidant and antiglycation properties might be more effective in treating the complications of diabetes mellitus [79, 80]. Almond skin is an abundant source of catechin, epicatechin, decreases hepatocyte cell death and ROS formation induced by an AGE product, gloxal [81]. Oral-treatments with anti-inflammatory and a conventional AGE-inhibitor, pyridoxamine, has been shown to inhibit AGE-induced ROS and inflammation in spinal structures and provide a potential treatment to slow progression of degenerative spine changes in diabetes [82]. The extract of the leaves of origanum majorana exerted beneficial effects on renal metabolic abnormalities, including AGEs formation and glycated collagen-linked fluorescence in diabetic animals, which were comparable with the effects of an antidiabetic drug glibenclamide [83]. The effects of other conventional reactive carbonyl species-trapping agents – including hydralazine, methoxylamine, aminoguanidine, carnosine, taurine and z-histidine hydrazide – have been compared with herbal compounds in several experiments, and it was found that cinnamon bark proanthocyanidins behave in a similar fashion to aminoguanidine, indicating great potential

to be developed as agents to alleviate diabetic complications [84]. Natural polyphenols including flavan-3-ols, tea flavins, cyanomaclurin, and dihydrochalcones or phenolic acids exert direct trapping agents of lipid peroxidation-derived adducts as acrolein and 4-hydroxy-trans2-nonenal (4-HNE) [85, 86]. In this context, we tested the effects of ethanolic seed and hull extracts of pomegranate for potential therapeutic use in the prevention of diabetic complications [72]. We also tested the flavonol quercetin [87] and oleuropein [55, 88], which were able to reduce the risk for diabetes production or diabetic complications, age-related protein dysfunctions or protein adduct formations via affecting different cellular cascades related with carbonyl stress. Olive leaf polyphenols are of special interest to our laboratory. Under the “OLEA project” the olive leaf polyphenolic mixture has demonstrated cytoprotective and anti-inflammatory properties in cardiomyocytes, insulin releasing β-cell or skin cell cultures stimulated by H2O2, 4-HNE or a cytokine cocktail [56, 57, 89, 90]. Our studies using diabetic models showed improved insulin sensitivity [57, 85], ameliorated antioxidant enzyme activity [27, 34, 35, 39, 41, 72], dysregulated glycated protein levels and lipid peroxidation products [34, 37, 41] by natural antioxidants. It is well known that a hallmark of glucotoxicity is a profound oxidative stress that may attenuate antioxidant defense in pancreatic β cells [56, 57, 91, 92]. As highlighted by our group, the classic pathway of glucotoxicity in β cells comes from the spontaneous reactions of glucose and other sugars with amine residues of proteins, lipids, and nucleic acids generating AGEs/ALEs. In pancreatic β cells, an antioxidant defense can be considered as low [57] and polyol pathway is activated when excess glucose is converted to sorbitol in the presence of aldose reductase, consuming NADPH and thus contributing to a prooxidation state [93, 94]. Moreover, new discoveries have identified NADPH oxidases in β cells as contributors to elevated cellular ROS, leading to β-cell dysfunction and failure [95]. β cell function may also be easily impaired under mild oxidative stress. Such stress also imposes activation of ROS-sensitive second messengers, such as p38MAPK [96], or JNK/SAPK [97] and then the β cell goes to apoptosis via caspases-dependent mechanisms without a significant increase in cytochrome c release [56]. Activation of the JNK pathway during oxidative stress results in decreased insulin gene expression by affecting the DNA binding activity of the epigenetic regulation of transcriptional factor pancreatic duodenal homeobox (PDX1) [98]. Thus, in turn, the beneficial effect of herbal antioxidants on the diabetic patient could be explained (in addition to the protection of oxidative destructions

60      Ergin et al.: Natural products against aging of macromolecules) by maintenance of PDX1. PDX1 plays pivotal role in proliferation, survival, and function of β cells and activation of insulin gene expression [99, 100]. The cytokine-induced β cell dysfunction and apoptosis are mediated by ROS signaling pathways [101, 102]. Cytokinegenerated ROS induce expression of inducible nitric oxide synthase (iNOS) which results in NO• release and translocation of NFκB. In turn, NFκB induces NADPH oxidase as a major cytosolic ROS source [103]. Recently it has been demonstrated that quercetin, quercitrin are potential candidates to prevent β-cell death via the mitochondrial pathway and NF-κB signaling, and quercetin may be more efficacious than quercitrin as an antidiabetic agent [104]. Similarly, myricetin protects against cytokine-induced cell death in RIN-m5f β cells [105], and naringenin inhibit cytokine-induced toxicity in β-cells by enhancing cell survival through PI3-kinase pathway, independent of p-p38 MAPK or iNOS [106]. According to these, under the OLEA projects we found that olive leaf polyphenolic mixture or olive leaf polyphenols, which are the special interest of our laboratory, had cytoprotective and anti-inflammatory effects tested in insulin releasing β-cell by H2O2, 4-hydroxy­ nonenal (4-HNE) or a cytokine cocktail [56, 57, 89, 90]. According to our experiments, kaempferol attenuates 4-hydroxynonenal-induced apoptosis in PC12 cells by directly inhibiting NADPH oxidase [107]. Several intervention studies have suggested that the consumption of flavonoid-, flavanone- or polyphenolic-rich foods such as tea, grape polyphenols, cocoa, pomegranate juice and soya can improve endothelial function in patients with manifest cardiovascular and cerebrovascular disease [108–111]. Consumption of a polyphenolic-rich diet can be effective at reducing cardiovascular disease risk factors, particularly with respect to anti-hypertensive effects, inhibition of platelet aggregation and increasing endothelial-dependent vasodilation [112, 113]. The studies performed with elderly people have demonstrated that the consumption of a Mediterranean diet produces an increase in NO bioavailability, with a consequent improvement in endothelial function and regeneration capacity [114]. Authors showed that the consumption of Mediterranean vegetables reduces postprandial levels of cellular stress biomarkers such as lipid peroxide, protein carbonyl, compared to a saturated fat-rich diet in metabolic syndrome subjects [115]. Others reported that monounsaturated fat consumption inhibits oxidative stress as compared to saturated fat by inducing higher postprandial antioxidant response in adipose tissue [116]. Similarly, monounsaturated fat consumption significantly attenuates a postprandial inflammatory state, including NF-κB, metalloproteinase-9 and tumor

necrosis factor-α [117, 118]. The findings of another study support that exogenous CoQ supplementation has protective effects against free radical over-generation through the lowering of postprandial oxidative stress modifying the postprandial antioxidant protein levels and reducing the postprandial expression of antioxidant genes in peripheral blood mononuclear cells [119]. Moreover, polyphenols, when used in conjunction with an intermittent feeding protocol, can enhance the longevity-promoting effects at least in mice [120].

Conclusion Large scale findings show that impaired physiological response of cells to the redox stressors associates with the early senescence and the accelerated aging of the organism. The contribution of carbonyl compounds and then protein adduct formations by advanced interaction of sugars/lipids with amino acids/peptides to the cell dysfunctions and abnormal redox metabolism are of great interest in recent research. The accumulation of adduct formation is also established in age-related diseases including Alzheimer’s, Parkinson’s, chronic obstructive pulmonary disease, cardiovascular diseases and diabetes. Plant extracts with polyphenolic compounds may increase health span. Natural cellular redox regulators such as polyphenols can enhance the longevity-promoting effects through the reduction of cellular degenerative chaos and inflammatory activity with a lower incidence of the diseases associated with aging. The growing evidence from definitive clinical trials and the present experimental findings at least in part have clear practical relevance for humans seeking to engage in health promoting behaviors. Acknowledgments: The authors acknowledge the support through the grants from the Scientific and Technical Research Council of Turkey (TUBITAK) (Project no. 106S025, 108S239, SBAG-3303), KOSGEB-2011–0850, Gazi University Research Foundation No: 01/2010–126, 01/2011– 09, 01/2012–70, Ankara University Research Foundation, Project No: 10B336002 (2011), COST Action B35 (Lipid Peroxidation Associated Disorders: LPO), COST-BM1203 (EU-ROS). They also thank FARMASENS Biotech Co., Gazi University Techno Park, Ankara, Turkey, (www.farmasens.com) for their support to E. Burcu Bali as research assistant and LongAgeHealth Co., Ankara, Turkey. Received June 25, 2013; accepted July 26, 2013; previously published online August 27, 2013

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Natural products and the aging process.

Abstract Literature surveys show that the most of the research that have been conducted on the effect of herbal remedies on many tissue pathologies, i...
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