Managing Oxidative Stress: Vitamin E’s Role in Reducing Cell Damage

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources : Oxidative stress, a condition caused by an imbalance between free radicals and antioxidants in the body, can lead to cell damage and various health problems. However, vitamin E has emerged as a potent defender against oxidative stress. As a powerful antioxidant, vitamin E plays a crucial role in neutralizing free radicals and preventing them from causing harm to cells. By scavenging these harmful molecules, vitamin E helps protect cell membranes and DNA from oxidative damage. Furthermore, it supports the proper functioning of the immune system and has been linked to a reduced risk of chronic diseases like heart disease and certain types of cancer. Including vitamin E-rich foods like nuts, seeds, and leafy greens in your diet can contribute to managing oxidative stress and promoting overall health.

Abstract

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Aging is the progressive loss of organ and tissue function over time. Growing older is positively linked to cognitive and biological degeneration such as physical frailty, psychological impairment, and cognitive decline. Oxidative stress is considered as an imbalance between pro- and antioxidant species, which results in molecular and cellular damage. Oxidative stress plays a crucial role in the development of age-related diseases. Emerging research evidence has suggested that antioxidant can control the autoxidation by interrupting the propagation of free radicals or by inhibiting the formation of free radicals and subsequently reduce oxidative stress, improve immune function, and increase healthy longevity. Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways. Therefore, the role of molecules with antioxidant activity that promote healthy aging and counteract oxidative stress is worth to discuss further. Of particular interest in this article, we highlighted the molecular mechanisms of antioxidants involved in the prevention of age-related diseases. Taken together, a better understanding of the role of antioxidants involved in redox modulation of inflammation would provide a useful approach for potential interventions, and subsequently promoting healthy longevity.

Introduction

The average life expectancy has increased rapidly over the past decades, with an average of around 71.4 years in 2015 worldwide (World Health Organization, 2018). In view of the demographics of the world population in between 2000 and 2050, the population over 60 years is expected to grow from 605 million to 2 billion people (World Health Organization, 2014). Although the increasing life expectancy reflects a positive human development, a new challenge is arising. In fact, growing older is positively linked to cognitive and biological degeneration such as physical frailty, psychological impairment, and cognitive decline (Jin et al., 2015).

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources : Age-related diseases have become the greatest health threats in the twenty-first century. Aging is an intrinsic, universal, multifactorial, and progressive process characterized as degenerative in nature, accompanied by progressive loss of function and ultimately increased mortality rate (Dabhade and Kotwal, 2013; López-Otín et al., 2013; Shokolenko et al., 2014; Chang et al., 2017). Among the theories that explain the aging process, the free radical theory of aging is long-established (Harman, 1956). This theory speculates that aging is a consequence of the failure of several defensive mechanisms to respond to the reactive oxygen species (ROS)-induced damage, particularly at the mitochondria (Islam, 2017). Age-related diseases are related to structural changes in mitochondria, accompanied by the alterations of biophysical properties of the membrane including alteration in the electron transport chain complexes activities, decreased fluidity, and subsequently resulted in energy imbalance and mitochondrial failure. These perturbations impair cellular homeostasis and mitochondrial function and enhance vulnerability to oxidative stress (Eckmann et al., 2013; Chistiakov et al., 2014). Elderly people are susceptible to oxidative stress due to a decline in the efficiency of their endogenous antioxidant systems. Organs such as brain and heart, with high rates of oxygen consumption and limited respiration levels, are particularly vulnerable to this phenomenon, hence partially explaining the high prevalence of cardiovascular diseases (CVD) and neurological disorders in elderly (Corbi et al., 2008).

Oxidative stress plays a crucial role in the development of age-related diseases including arthritis, diabetes, dementia, cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, and metabolic syndromes (Tan et al., 2015a; Liu et al., 2017). ROS are generated within the biological system to modulate the cellular activities such as cell survival, stressor responses, and inflammation (He and Zuo, 2015; Zuo et al., 2015). Elevation of ROS has been associated with the onset and progression of aging. Although ROS generation may not be an essential factor for aging (López-Otín et al., 2013), they are more likely to exacerbate age-related diseases progression via oxidative damage and interaction with mitochondria (Dias et al., 2013). Due to their reactivity, high concentrations of ROS can cause oxidative stress by disrupting the balance of antioxidant and prooxidant levels (Zuo et al., 2015). Emerging research evidence has suggested that natural compounds can reduce oxidative stress and improve immune function (Ricordi et al., 2015). Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways. Therefore, the role of molecules with antioxidant activity that promote healthy aging and counteract oxidative stress is worth to discuss further. Of particular interest in this article, we highlighted the molecular mechanisms of antioxidants involved in the prevention of age-related diseases. An in-depth understanding of the role of antioxidants involved in redox modulation of inflammation would provide a useful approach for potential interventions, and subsequently promoting healthy longevity.

Redox imbalance in age-related diseases

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources :  In the last few decades, several models have been suggested to define the interconnection and the biological pathways of aging (Dice, 1993). The widely accepted theory is the “oxidative stress hypothesis” (Ghezzi et al., 2017) that advanced and modified the free radical theory of aging (Harman, 1956). Based on the oxidative stress hypothesis, oxidative damage is not solely triggered by the unrestricted ROS production, but it also caused by other oxidants, such as reactive lipid species and reactive nitrogen species (RNS). The hypothesis of oxidative stress highlights the crucial role of antioxidant defenses as an important component of the overall redox balance of the organism. However, several studies demonstrated that avoiding oxidative stress damage does not increase longevity (Buffenstein et al., 2008; Pérez et al., 2009a,b).

Oxidative stress is considered as an imbalance between pro- and antioxidant species, which results in molecular and cellular damage (Conti et al., 2016). Mitochondria are major organelles that are accountable for generation of energy through oxidative phosphorylation to generate adenosine triphosphate (ATP), a molecule which is crucial for cellular actions (Weinberg et al., 2015). The electron transport chain consumes up to 90% of total oxygen (O2) taken up by the cells (Wallace, 2013). During this process, ROS are generated as by-products for the partial four-electron reduction of O2 to produce water molecule, which is the last electron acceptor in the ATP generation process (Ambrosio et al., 1993). Nearly 0.1–0.5% of inhaled O2 is converted to superoxide (O−2) during the normal physiological states (Servais et al., 2009). In the normal healthy state, the generation and oxidation of ROS occur in a controlled manner. By contrast, the ROS production is increased under high-stress conditions or under disease states. The ROS generated from aerobic respiration caused a cumulative oxidative damage in macromolecules, including lipids, DNA, and proteins, which subsequently lead to cells death (Scheibye-Knudsen et al., 2015), and affect the healthspan of numerous principal organ systems (Dai et al., 2014).

An alteration of the redox status and the dysregulation of the immune system during aging may lead to the elevation of systemic inflammatory status. Both of these processes caused the activation of inflammatory mediators via oxidative stress-induced redox imbalance. The age-related redox imbalance is more likely triggered by the net effect of low antioxidative defense systems and incessantly produce of reactive species, including superoxide (O−2), hydroxyl radical (•OH), peroxynitrite (ONOO−), hydrogen peroxide (H2O2), reactive lipid aldehydes, and reactive nitric oxide (NO) (Chung et al., 2009; Lennicke et al., 2015). Unresolved chronic inflammation during aging may serve as a pathophysiologic association which converts normal functional changes to the age-related degenerative diseases (Viola and Soehnlein, 2015). Oxidative stress is reinforced by several reactive species, including H2O2, singlet oxygen, other radicals, and non-radicals, which are consistently produced in the body due to the aerobic metabolism, and thereby potentially altering basic structural components such as proteins, lipids, and nucleic acids (Weidinger and Kozlov, 2015).

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources :  Template biosynthesis of polypeptide chains on ribosomes usually does not produce a functional protein. The newly developed polypeptide chain must undergo certain chemical modifications outside the ribosome. Thus, these modifications are most often accompanied by enzymes and take place after all the information supplied by the template RNA (mRNA) has been read, that is after mRNA translation. These additional processes are known as posttranslational modifications. There are four primary groups of protein functions which require posttranslational modification of amino acid residue side chains. The functional activity of several proteins requires the presence of certain prosthetic groups covalently bound to the polypeptide chain. These are usually involving complex organic molecules which take part in the protein activity for instance, the transformation of inactive apoproteins into enzymes. Another important group of modifications is protein tags, which provide intracellular localization of proteins such as marking the proteins for transport to the proteasome, where they will be proteolyzed and hydrolyzed. Additionally, some of the posttranslational modifications regulate biochemical processes by varying enzymatic activity (Knorre et al., 2009).

Naturally, the organism has several antioxidant defenses to protect against hostile oxidative environments, including classical antioxidant enzymes for example catalase, glutathione peroxidase, and superoxide dismutase as well as non-enzymatic ROS scavengers, such as β-carotene, vitamin C, vitamin E, and uric acid (Espinosa-Diez et al., 2015; Harris et al., 2015). Among all the antioxidant enzymes, glutathione peroxidase is the most powerful biological antioxidative reductant (Cross et al., 1977). Collectively, maintaining a healthy redox balance status is crucial for the physiological acid-base buffer system in the body for the optimal homeostatic cellular activities. Changing in redox balance would have a great impact on the transcriptional activities and cellular signaling pathways because most of the activation and reactions is dependent on the reduction/oxidation processes. Figure ​Figure11 shows the effect of oxidative stress and the interaction of aging and age-related diseases.

Chronic inflammation and aging (inflammaging)

Inflammaging is a chronic, low-grade, and systemic inflammation in aging, which is occurred in the absence of overt infection (Franceschi and Campisi, 2014). Chronic inflammation is usually derived from the damaged cells or macromolecules due to an inadequate elimination or increased production. The ability of gut to sequester harmful microbes declines with age. Therefore, some of the harmful products that produced by the microbial constituents of the human body, such as gut microbiota, is capable to permeable into surrounding tissues (Biagi et al., 2011), and subsequently leading to chronic low-grade inflammation.

Senescence, a cellular response to stress and other damage (Franceschi and Campisi, 2014). Persistent senescent cells have been associated with aging or age-related diseases via  wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources :  secretion of proinflammatory cytokines that alter the tissue microenvironment or modify the function of normal cells (Baker et al., 2011). The study reported by Coppé et al. (2010) demonstrated that elimination of senescent cells in prematurely aged mice can prevent many age-related diseases. Increased inflammation may also derive from the stimulation of coagulation system. Coagulation is regarded as a part of the inflammation system. Aging promotes the hypercoagulable state and increased the risk of arterial and venous thrombosis in the elderly (Franceschi and Campisi, 2014). Additionally, aging also alters the immune system, which is subsequently leading to inflammaging. Adaptive immunity decreases with age; conversely, innate immunity demonstrated minute changes in mild hyperactivity (Santoro et al., 2018). The response of innate immunity might increase when adaptive immunosenescence progresses. These age-related changes could be due to the lifelong exposure to antigens and pathogens, as well as intrinsic changes in immune cells (Stephenson et al., 2018).

Molecular inflammation involved during aging

Numerous age-related diseases undergo the inflammation process, which is a risk factor in or partly of disease development (DeBalsi et al., 2017). For instance, several age-related diseases including diabetes, dementia, metabolic syndrome, osteoporosis, cancer, arthritis, and cardiovascular diseases have been recognized as inflammatory disorders (Tan et al., 2015b; Abbas et al., 2017; Liu et al., 2017). The interaction between inflammation and oxidative stress is tightly associated with the prostaglandins (PGs) biosynthetic pathway that produces reactive species (Kawahara et al., 2015). PGs are lipid metabolites of arachidonic acid which have strong proinflammatory responses with pathogenic activities. For example, certain PG metabolites act as an active mediator of inflammation. While, some of the reactive species produced from PGs metabolism may exacerbate inflammation and induce tissue damage (Blaser et al., 2016). Cyclooxygenase (COX) is a predominant enzyme in the PG synthetic pathway, which produces prostaglandin H2 (PGH2) from arachidonic acid (Shehzad et al., 2015). Reactive species are generated during the conversion of prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) (Rashid, 2017). The production of reactive species via PG synthesis pathway contributes significantly to the overall reactive species pool in both pathological and normal states, especially during aging (Nita and Grzybowski, 2016).

Research evidence has suggested that the molecular inflammatory process plays a vitally important role during the aging process and age-related diseases (Davalli et al., 2016). COX-derived reactive species and transcriptional activity of interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) are increased during aging (Michaud et al., 2013; Zhang and Jiang, 2015; Puzianowska-Kuznicka et al., 2016). Other pro-inflammatory proteins such as vascular cell adhesion molecule 1 (VCAM-1), P- and E-selectin, and intercellular adhesion molecule 1 (ICAM-1), are all enhanced during aging (Biswas, 2016).

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources :  The nuclear factor-kappa B (NF-κB) transcription factor has been identified as the key factor during inflammation which can be stimulated by oxidative stimuli. In fact, the stimulation of NF-κB-dependent genes is a principal culprit that is responsible for the systemic inflammatory process (Golia et al., 2014). Under high- stress circumstances, proinflammatory genes encode proinflammatory proteins, including chemokines, growth factors, and cytokines. NF-κB activity is mediated by numerous signaling pathways such as mitogen-activated protein kinases (MAPKs) and IκB kinase (IKK). The upregulation of IKK complexes phosphorylate the IκB subunits of NF-κB/IκB and subsequently activate the NF-κB (Jain et al., 2016). IKK activity is triggered during aging by NF-κB (Kim et al., 2002), which further modulates the p38 MAPK, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases (JNKs) pathways that modulate the NF-κB-dependent transcriptional activity during the inflammatory reaction. ROS production during the aging process has been associated with p38 MAPK, JNK, and ERK activities (Zhang et al., 2015). Nonetheless, uncontrolled input signal during aging may cause chronic proinflammatory conditions that are conducive to various chronic diseases (Fougère et al., 2017). Aging is also linked to the elevation of inflammatory cell (monocytes and neutrophil) counts and C-reactive protein (CRP) levels (Tang et al., 2017). High IL-6 plasma levels were shown to have a greater likelihood of mortality, morbidity, and disability in the elderly (Puzianowska-Kuznicka et al., 2016). Indeed, high plasma level of TNF-α is associated with a marked increase in CRP and IL-6, suggesting an interrelated stimulation of the entire inflammatory cascade (Xia et al., 2016).

In addition, compelling evidence suggests that DNA damage response (DDR) signaling is a predominant mechanism associated with the build-up of DNA damage, aging, and cell senescence (Malaquin et al., 2015). This study indicates the involvement of epigenetic modifications such as small, non-coding RNAs and microRNAs, which contributes to post-transcriptional regulation. These modifications have been hypothesized to play a crucial role in the diffusion of DNA damage response/senescence-associated secretory phenotype (DDR/SAPS) signaling to non-damaged surrounding cells during aging, suggesting that DDR/SASP signaling components may contribute to the development of novel therapeutic interventions against age-related diseases (Olivieri et al., 2015). Moreover, microRNAs may also be harnessed as an innovative tool to identify target senescent cells and to develop therapeutic interventions that can delay the proinflammatory programme stimulated in senescent endothelial cells (Prattichizzo et al., 2016).

Accelerated-aging syndromes

wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources :  Progerias or accelerated-aging syndromes are partially recapitulated normal aging (Burtner and Kennedy, 2010). Most of the accelerated-aging syndromes are induced by modification of nuclear envelope or by defects in DNA repair systems. Werner syndrome is the most common accelerated-aging syndrome derived from DNA repair defects, caused by the mutations of Werner syndrome ATP-dependent helicase (WRN), a gene coding for a protein implicated in telomere maintenance and homology-dependent recombination repair (Osorio et al., 2011). Another common accelerated-aging syndrome is Hutchinson-Gilford progeria syndrome (HGPS), caused by the defects in nuclear envelope proteins due to the mutations in the processing protease FACE1/ZMPSTE24 or genes encoding lamin A (Worman, 2012). Compared to HGPS, the onset of Werner syndrome is slightly slower, in which the pathology accompanies with Werner syndrome resembles a premature aging. Clinical pathology of Werner syndrome starting from 10 to 20 years of age including early graying, short stature, hair loss, and bilateral cataracts. The cellular phenotypes linked to the Werner syndrome demonstrate significant overlap with laminopathies. Further, cells in the absence of WRN have defects in DNA double-strand breaks, especially those bound with DNA replication fork arrest.

Interestingly, the generation of ROS is increased in HGPS fibroblasts (Viteri et al., 2010) and this phenomenon is similar to normal aged fibroblasts. High ROS level in HGPS cells could be attributed to the large DNA damage and subsequently resulting in an underlying defect in early senescence in HGPS cells (Huang et al., 2005; Gonzalez-Suarez et al., 2009). HGPS cells also show persistent markers of high basal DNA damage, such as nuclear ataxia telangiectasia mutated (ATM) foci (Liu Y. et al., 2006). The previous study showed that fibroblasts isolated from individuals with HGPS demonstrate lamin A has an ability to repair DNA lesions (Burtner and Kennedy, 2010).

Mutation in lamin A/C (LMNA) has been identified as the target gene for HGPS. Fibroblasts from patients with HGPS show increased levels of basal phosphorylated histone variant H2AX (γH2AX) and increased amounts of phosphorylated checkpoint kinase 1 (CHK1) and CHK2, compared with unaffected fibroblasts (Liu Y. et al., 2006). In addition, fibroblasts from individuals affected by HGPS, or from mice lacking ZmPSTe24, demonstrate a marked delay in the recruitment of p53 binding protein 1 (53BP1) to sites of DNA repair upon exposure to DSB-inducing irradiation (Liu et al., 2005). The delay in 53BP1 recruitment to DSBs in these cells and the accumulation of irreparable damage may be a potent physiological genotoxic stress in individuals with HGPS. Collectively, increased levels of DNA damage may have important consequences in vivo.

Antioxidant and age-related diseases

Antioxidants control the autoxidation by interrupting the propagation of free radicals or by inhibiting the formation of free radicals via different mechanisms. These compounds help in scavenging the species that initiate the peroxidation, breaking the autoxidative chain reaction, quenching •O−2, and preventing the formation of peroxides (Gaschler and Stockwell, 2017). The most effective antioxidants are those possessing the ability to interfere with the free radical chain reaction. They contain phenolic or aromatic rings which allow these antioxidants donate H• to the free radicals formed during oxidation. The radical intermediate is then stabilized by the resonance delocalization of the electron within the aromatic ring (Wojtunik-Kulesza et al., 2016).

Antioxidant plays a central role in the termination of oxidative chain reactions by removing the free radical intermediates (Gholamian-Dehkordi et al., 2017). Many studies indicate that cellular redox status is crucial for ROS-mediated signaling  wellhealthorganic.com:vitamin-e-health-benefits-and-nutritional-sources : and mitochondrial function (Fang et al., 2018). Depletion of intracellular glutathione (GSH) markedly promotes mitochondrial ROS production and triggers mitochondrial membrane depolarization (Lohan et al., 2018). Stimulation of the Nrf2/ARE pathway is fundamental for the induction of antioxidant defense enzyme and the modulation of the intracellular GSH in response to stress (Liu et al., 2018a). Administration of N-acetylcysteine reverses GSH depletion and restores ARE-associated transcriptional activity to basal levels (Limón-Pacheco et al., 2007). Appropriate intracellular levels of ROS plays a crucial role in physiological redox signaling via activation and regulation of endogenous defenses by protecting cells from nitrosative, oxidative, and electrophilic stress (Moldogazieva et al., 2018). Indeed, supplementation with exogenous antioxidants depletes exercise-triggered improvements in insulin sensitivity and antioxidant gene expression (Ji et al., 2006), suggesting the importance of ROS induced endogenous antioxidant enzymes in restoring physiological redox balance. Additionally, overexpression of thioredoxin (Trx) has been demonstrated to inhibit the progression of insulin resistance in both type 1 and type 2 diabetes in vivo (Yamamoto et al., 2008). Recent findings suggest that a protective role of Nrf2 on oxidative stress in aging (de Oliveira et al., 2018). Depletion of Nrf2 activity has been identified to contribute to the development of age-related diseases (Cuadrado et al., 2018).

Several studies as reported by Tan et al. (2018) have shown that oxidative stress and obesity-associated non-communicable diseases (NCDs) can be mediated by nutrient-rich in antioxidants. Indeed, a unique complex of bioactive constituents can provide protection against oxidative stress, which can cause in inflammation (Tan et al., 2015a,b; Tan and Norhaizan, 2017). In support of this, numerous epidemiological studies including European paradox study (Bellizzi et al., 1994), WHO/MONICA study (Gey and Puska, 1989), NHS study (Stampfer et al., 1993), and Harvard HPSF (Rimm et al., 1993) have shown that antioxidant was negatively associated with many NCDs including cardiovascular diseases. In this regard, the antioxidant capacity in natural products has drawn attention among scientists in academia and industry in the prevention of age-related diseases. Figure ​Figure22 summarizes the dietary intake of antioxidants in relation to oxidative stress in aging.