Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases

REVIEW
published: 16 October 2018

doi: 10.3389/fphar.2018.01162
Antioxidant and Oxidative Stress: A

Mutual Interplay in Age-Related
Diseases
Bee Ling Tan 1 , Mohd Esa Norhaizan 1,2,3*, Winnie-Pui-Pui Liew 1 and
Heshu Sulaiman Rahman 4†
1
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor,
Malaysia, 2 Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia,
3
Research Centre of Excellent, Nutrition and Non-Communicable Diseases (NNCD), Faculty of Medicine and Health
Sciences, Universiti Putra Malaysia, Selangor, Malaysia, 4 College of Veterinary Medicine, University of Sulaimani, Sulaimani,
Iraq
Aging is the progressive loss of organ and tissue function over time. Growing older
Edited by:
is positively linked to cognitive and biological degeneration such as physical frailty,
Andres Trostchansky, psychological impairment, and cognitive decline. Oxidative stress is considered as
Universidad de la República, Uruguay
an imbalance between pro- and antioxidant species, which results in molecular and
Reviewed by:
cellular damage. Oxidative stress plays a crucial role in the development of age-related
Suowen Xu,
University of Rochester, United States diseases. Emerging research evidence has suggested that antioxidant can control the
Veronica Demicheli, autoxidation by interrupting the propagation of free radicals or by inhibiting the formation
Universidad de la República, Uruguay
of free radicals and subsequently reduce oxidative stress, improve immune function, and
*Correspondence:
Mohd Esa Norhaizan
increase healthy longevity. Indeed, oxidation damage is highly dependent on the inherited
[email protected] or acquired defects in enzymes involved in the redox-mediated signaling pathways.
† Present Address: Therefore, the role of molecules with antioxidant activity that promote healthy aging
Heshu Sulaiman Rahman, and counteract oxidative stress is worth to discuss further. Of particular interest in
Faculty of Biotechnology and
this article, we highlighted the molecular mechanisms of antioxidants involved in the
Biomolecular Sciences, Universiti
Putra Malaysia, Selangor, Malaysia; prevention of age-related diseases. Taken together, a better understanding of the role
College of Veterinary Medicine, of antioxidants involved in redox modulation of inflammation would provide a useful
University of Sulaimani, Sulaimani, Iraq
approach for potential interventions, and subsequently promoting healthy longevity.
Specialty section: Keywords: age-related diseases, healthy longevity, inflammation, oxidative stress, oxidative damage
This article was submitted to
Experimental Pharmacology and Drug
Discovery,
INTRODUCTION
a section of the journal
Frontiers in Pharmacology
The average life expectancy has increased rapidly over the past decades, with an average of around
Received: 30 May 2018 71.4 years in 2015 worldwide (World Health Organization, 2018). In view of the demographics
Accepted: 24 September 2018 of the world population in between 2000 and 2050, the population over 60 years is expected
Published: 16 October 2018
to grow from 605 million to 2 billion people (World Health Organization, 2014). Although the
Citation: increasing life expectancy reflects a positive human development, a new challenge is arising. In
Tan BL, Norhaizan ME, Liew W-P-P
fact, growing older is positively linked to cognitive and biological degeneration such as physical
and Sulaiman Rahman H (2018)
Antioxidant and Oxidative Stress: A
frailty, psychological impairment, and cognitive decline (Jin et al., 2015).
Mutual Interplay in Age-Related Age-related diseases have become the greatest health threats in the twenty-first century. Aging
Diseases. Front. Pharmacol. 9:1162. is an intrinsic, universal, multifactorial, and progressive process characterized as degenerative
doi: 10.3389/fphar.2018.01162 in nature, accompanied by progressive loss of function and ultimately increased mortality rate
Frontiers in Pharmacology | www.frontiersin.org 1 October 2018 | Volume 9 | Article 1162

Tan et al. Antioxidant and Age-Related Diseases
(Dabhade and Kotwal, 2013; López-Otín et al., 2013; Shokolenko the balance of antioxidant and prooxidant levels (Zuo et al.,
et al., 2014; Chang et al., 2017). Among the theories that 2015). Emerging research evidence has suggested that natural
explain the aging process, the free radical theory of aging is compounds can reduce oxidative stress and improve immune
long-established (Harman, 1956). This theory speculates that function (Ricordi et al., 2015). Indeed, oxidation damage is
aging is a consequence of the failure of several defensive highly dependent on the inherited or acquired defects in enzymes
mechanisms to respond to the reactive oxygen species (ROS)- involved in the redox-mediated signaling pathways. Therefore,
induced damage, particularly at the mitochondria (Islam, the role of molecules with antioxidant activity that promote
2017). Age-related diseases are related to structural changes in healthy aging and counteract oxidative stress is worth to discuss
mitochondria, accompanied by the alterations of biophysical further. Of particular interest in this article, we highlighted
properties of the membrane including alteration in the electron the molecular mechanisms of antioxidants involved in the
transport chain complexes activities, decreased fluidity, and prevention of age-related diseases. An in-depth understanding
subsequently resulted in energy imbalance and mitochondrial of the role of antioxidants involved in redox modulation of
failure. These perturbations impair cellular homeostasis and inflammation would provide a useful approach for potential
mitochondrial function and enhance vulnerability to oxidative interventions, and subsequently promoting healthy longevity.
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 REDOX IMBALANCE IN AGE-RELATED
such as brain and heart, with high rates of oxygen consumption DISEASES
and limited respiration levels, are particularly vulnerable to this
phenomenon, hence partially explaining the high prevalence of In the last few decades, several models have been suggested
cardiovascular diseases (CVD) and neurological disorders in to define the interconnection and the biological pathways of
elderly (Corbi et al., 2008). aging (Dice, 1993). The widely accepted theory is the “oxidative
Oxidative stress plays a crucial role in the development stress hypothesis” (Ghezzi et al., 2017) that advanced and
of age-related diseases including arthritis, diabetes, dementia, modified the free radical theory of aging (Harman, 1956). Based
cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, on the oxidative stress hypothesis, oxidative damage is not
and metabolic syndromes (Tan et al., 2015a; Liu et al., 2017). solely triggered by the unrestricted ROS production, but it also
ROS are generated within the biological system to modulate the caused by other oxidants, such as reactive lipid species and
cellular activities such as cell survival, stressor responses, and reactive nitrogen species (RNS). The hypothesis of oxidative
inflammation (He and Zuo, 2015; Zuo et al., 2015). Elevation of stress highlights the crucial role of antioxidant defenses as
ROS has been associated with the onset and progression of aging. an important component of the overall redox balance of the
Although ROS generation may not be an essential factor for aging organism. However, several studies demonstrated that avoiding
(López-Otín et al., 2013), they are more likely to exacerbate age- oxidative stress damage does not increase longevity (Buffenstein
related diseases progression via oxidative damage and interaction et al., 2008; Pérez et al., 2009a,b).
with mitochondria (Dias et al., 2013). Due to their reactivity, high Oxidative stress is considered as an imbalance between pro-
concentrations of ROS can cause oxidative stress by disrupting and antioxidant species, which results in molecular and cellular
damage (Conti et al., 2016). Mitochondria are major organelles
Abbreviations: ABCA1, adenosine triphosphate-binding cassette transporter that are accountable for generation of energy through oxidative
A1; AMD, age-related macular degeneration; ATP, adenosine triphosphate; phosphorylation to generate adenosine triphosphate (ATP), a
COX, cyclooxygenase; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DDR, molecule which is crucial for cellular actions (Weinberg et al.,
DNA damage response; ERK, extracellular signal-regulated kinase; GLUT1,
2015). The electron transport chain consumes up to 90% of
glucose transporter type 1; GSNO, S-nitroglutathione; GSTα, α-glutathione
S-transferase; HDL, high-density lipoprotein; HGPS, Hutchinson-Gilford progeria total oxygen (O2 ) taken up by the cells (Wallace, 2013). During
syndrome; HO-1, heme oxygenase-1; H2O2, hydrogen peroxide; ICAM-1, this process, ROS are generated as by-products for the partial
intercellular adhesion molecule 1; IKK, IκB kinase; IL-1β, interleukin-1beta; four-electron reduction of O2 to produce water molecule, which
iNOS, inducible nitric oxide synthase; IL-6, interleukin-6; JNKs, c-Jun N-terminal is the last electron acceptor in the ATP generation process
kinases; LPS, lipopolysaccharide; MAPKs, mitogen-activated protein kinases;
(Ambrosio et al., 1993). Nearly 0.1–0.5% of inhaled O2 is
MHC, major histocompatibility complex; MMP-1, matrix metalloproteinase-
1; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine converted to superoxide (O− 2 ) during the normal physiological
dinucleotide phosphate; NADPH-oxidase, nicotinamide adenine dinucleotide states (Servais et al., 2009). In the normal healthy state, the
phosphate-oxidase; NCDs, non-communicable diseases; NF-κB, nuclear factor- generation and oxidation of ROS occur in a controlled manner.
kappa B; NO, nitric oxide; Nrf-2, nuclear factor E2-related factor 2; O2, By contrast, the ROS production is increased under high-stress
oxygen; O2•, superoxide; •OH, hydroxyl radical; ONOO− , peroxynitrite; oxLDL,
oxidized-low density lipoprotein; PAI-1, plasminogen activator inhibitor-1; PGs,
conditions or under disease states. The ROS generated from
prostaglandins; PGG2, prostaglandin G2; PGH2, prostaglandin H2; PKC, protein aerobic respiration caused a cumulative oxidative damage in
kinase C; PPARγ, peroxisome proliferator-activated receptor gamma; PP2A, macromolecules, including lipids, DNA, and proteins, which
phosphoprotein phosphatase 2A; PUFAs, polyunsaturated fatty acids; RANKL, subsequently lead to cells death (Scheibye-Knudsen et al., 2015),
receptor activator of nuclear factor kappa B ligand; RNS, reactive nitrogen species; and affect the healthspan of numerous principal organ systems
ROS, reactive oxygen species; SAPS, senescence-associated secretory phenotype;
TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor-α; TPP,
(Dai et al., 2014).
triphenylphosphonium; Trx, thioredoxin; UQ, ubiquinone; VCAM-1, vascular cell An alteration of the redox status and the dysregulation of
adhesion molecule 1; 5-LOX, 5-lipoxygenase. the immune system during aging may lead to the elevation of

systemic inflammatory status. Both of these processes caused CHRONIC INFLAMMATION AND AGING
the activation of inflammatory mediators via oxidative stress- (INFLAMMAGING)
induced redox imbalance. The age-related redox imbalance is
more likely triggered by the net effect of low antioxidative defense Inflammaging is a chronic, low-grade, and systemic
systems and incessantly produce of reactive species, including inflammation in aging, which is occurred in the absence
superoxide (O− 2 ), hydroxyl radical (•OH), peroxynitrite of overt infection (Franceschi and Campisi, 2014). Chronic
(ONOO− ), hydrogen peroxide (H2 O2 ), reactive lipid aldehydes, inflammation is usually derived from the damaged cells or
and reactive nitric oxide (NO) (Chung et al., 2009; Lennicke macromolecules due to an inadequate elimination or increased
et al., 2015). Unresolved chronic inflammation during aging production. The ability of gut to sequester harmful microbes
may serve as a pathophysiologic association which converts declines with age. Therefore, some of the harmful products that
normal functional changes to the age-related degenerative produced by the microbial constituents of the human body, such
diseases (Viola and Soehnlein, 2015). Oxidative stress is as gut microbiota, is capable to permeable into surrounding
reinforced by several reactive species, including H2 O2 , singlet tissues (Biagi et al., 2011), and subsequently leading to chronic
oxygen, other radicals, and non-radicals, which are consistently low-grade inflammation.
produced in the body due to the aerobic metabolism, and Senescence, a cellular response to stress and other damage
thereby potentially altering basic structural components such (Franceschi and Campisi, 2014). Persistent senescent cells
as proteins, lipids, and nucleic acids (Weidinger and Kozlov, have been associated with aging or age-related diseases via
2015). secretion of proinflammatory cytokines that alter the tissue
Template biosynthesis of polypeptide chains on ribosomes microenvironment or modify the function of normal cells
usually does not produce a functional protein. The newly (Baker et al., 2011). The study reported by Coppé et al.
developed polypeptide chain must undergo certain chemical (2010) demonstrated that elimination of senescent cells in
modifications outside the ribosome. Thus, these modifications prematurely aged mice can prevent many age-related diseases.
are most often accompanied by enzymes and take place after Increased inflammation may also derive from the stimulation
all the information supplied by the template RNA (mRNA) of coagulation system. Coagulation is regarded as a part of
has been read, that is after mRNA translation. These additional the inflammation system. Aging promotes the hypercoagulable
processes are known as posttranslational modifications. There state and increased the risk of arterial and venous thrombosis
are four primary groups of protein functions which require in the elderly (Franceschi and Campisi, 2014). Additionally,
posttranslational modification of amino acid residue side aging also alters the immune system, which is subsequently
chains. The functional activity of several proteins requires leading to inflammaging. Adaptive immunity decreases with age;
the presence of certain prosthetic groups covalently bound to conversely, innate immunity demonstrated minute changes in
the polypeptide chain. These are usually involving complex mild hyperactivity (Santoro et al., 2018). The response of innate
organic molecules which take part in the protein activity immunity might increase when adaptive immunosenescence
for instance, the transformation of inactive apoproteins progresses. These age-related changes could be due to the lifelong
into enzymes. Another important group of modifications exposure to antigens and pathogens, as well as intrinsic changes
is protein tags, which provide intracellular localization of in immune cells (Stephenson et al., 2018).
proteins such as marking the proteins for transport to the
proteasome, where they will be proteolyzed and hydrolyzed.
Additionally, some of the posttranslational modifications MOLECULAR INFLAMMATION INVOLVED
regulate biochemical processes by varying enzymatic activity DURING AGING
(Knorre et al., 2009).
Naturally, the organism has several antioxidant defenses Numerous age-related diseases undergo the inflammation
to protect against hostile oxidative environments, including process, which is a risk factor in or partly of disease
classical antioxidant enzymes for example catalase, glutathione development (DeBalsi et al., 2017). For instance, several
peroxidase, and superoxide dismutase as well as non-enzymatic age-related diseases including diabetes, dementia, metabolic
ROS scavengers, such as β-carotene, vitamin C, vitamin E, syndrome, osteoporosis, cancer, arthritis, and cardiovascular
and uric acid (Espinosa-Diez et al., 2015; Harris et al., 2015). diseases have been recognized as inflammatory disorders (Tan
Among all the antioxidant enzymes, glutathione peroxidase is et al., 2015b; Abbas et al., 2017; Liu et al., 2017). The
the most powerful biological antioxidative reductant (Cross interaction between inflammation and oxidative stress is tightly
et al., 1977). Collectively, maintaining a healthy redox balance associated with the prostaglandins (PGs) biosynthetic pathway
status is crucial for the physiological acid-base buffer system that produces reactive species (Kawahara et al., 2015). PGs
in the body for the optimal homeostatic cellular activities. are lipid metabolites of arachidonic acid which have strong
Changing in redox balance would have a great impact on proinflammatory responses with pathogenic activities. For
the transcriptional activities and cellular signaling pathways example, certain PG metabolites act as an active mediator of
because most of the activation and reactions is dependent on inflammation. While, some of the reactive species produced
the reduction/oxidation processes. Figure 1 shows the effect of from PGs metabolism may exacerbate inflammation and induce
oxidative stress and the interaction of aging and age-related tissue damage (Blaser et al., 2016). Cyclooxygenase (COX) is
diseases. a predominant enzyme in the PG synthetic pathway, which

FIGURE 1 | Effect of oxidative stress and the interaction of aging and age-related diseases. Accumulation of reactive oxygen species (ROS) leads to mRNA damage
and lipid/protein oxidation and subsequently causes a decrease in mitochondrial function, and ultimately produces more oxidative stress. Mitochondrial function
decline and oxidative stress response in aging may subsequently contribute to age-related diseases.
produces prostaglandin H2 (PGH2 ) from arachidonic acid stimulation of NF-κB-dependent genes is a principal culprit
(Shehzad et al., 2015). Reactive species are generated during the that is responsible for the systemic inflammatory process (Golia
conversion of prostaglandin G2 (PGG2 ) to prostaglandin H2 et al., 2014). Under high- stress circumstances, proinflammatory
(PGH2 ) (Rashid, 2017). The production of reactive species via PG genes encode proinflammatory proteins, including chemokines,
synthesis pathway contributes significantly to the overall reactive growth factors, and cytokines. NF-κB activity is mediated by
species pool in both pathological and normal states, especially numerous signaling pathways such as mitogen-activated protein
during aging (Nita and Grzybowski, 2016). kinases (MAPKs) and IκB kinase (IKK). The upregulation of IKK
Research evidence has suggested that the molecular complexes phosphorylate the IκB subunits of NF-κB/IκB and
inflammatory process plays a vitally important role during subsequently activate the NF-κB (Jain et al., 2016). IKK activity
the aging process and age-related diseases (Davalli et al., 2016). is triggered during aging by NF-κB (Kim et al., 2002), which
COX-derived reactive species and transcriptional activity of further modulates the p38 MAPK, extracellular signal-regulated
interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis kinase (ERK), and c-Jun N-terminal kinases (JNKs) pathways
factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible that modulate the NF-κB-dependent transcriptional activity
nitric oxide synthase (iNOS) are increased during aging during the inflammatory reaction. ROS production during the
(Michaud et al., 2013; Zhang and Jiang, 2015; Puzianowska- aging process has been associated with p38 MAPK, JNK, and
Kuznicka et al., 2016). Other pro-inflammatory proteins such ERK activities (Zhang et al., 2015). Nonetheless, uncontrolled
as vascular cell adhesion molecule 1 (VCAM-1), P- and E- input signal during aging may cause chronic proinflammatory
selectin, and intercellular adhesion molecule 1 (ICAM-1), are all conditions that are conducive to various chronic diseases
enhanced during aging (Biswas, 2016). (Fougère et al., 2017). Aging is also linked to the elevation
The nuclear factor-kappa B (NF-κB) transcription factor of inflammatory cell (monocytes and neutrophil) counts and
has been identified as the key factor during inflammation C-reactive protein (CRP) levels (Tang et al., 2017). High IL-
which can be stimulated by oxidative stimuli. In fact, the 6 plasma levels were shown to have a greater likelihood of

mortality, morbidity, and disability in the elderly (Puzianowska- ataxia telangiectasia mutated (ATM) foci (Liu Y. et al., 2006). The
Kuznicka et al., 2016). Indeed, high plasma level of TNF-α is previous study showed that fibroblasts isolated from individuals
associated with a marked increase in CRP and IL-6, suggesting an with HGPS demonstrate lamin A has an ability to repair DNA
interrelated stimulation of the entire inflammatory cascade (Xia lesions (Burtner and Kennedy, 2010).
et al., 2016). Mutation in lamin A/C (LMNA) has been identified as the
In addition, compelling evidence suggests that DNA damage target gene for HGPS. Fibroblasts from patients with HGPS
response (DDR) signaling is a predominant mechanism show increased levels of basal phosphorylated histone variant
associated with the build-up of DNA damage, aging, and H2AX (γH2AX) and increased amounts of phosphorylated
cell senescence (Malaquin et al., 2015). This study indicates checkpoint kinase 1 (CHK1) and CHK2, compared with
the involvement of epigenetic modifications such as small, unaffected fibroblasts (Liu Y. et al., 2006). In addition, fibroblasts
non-coding RNAs and microRNAs, which contributes to from individuals affected by HGPS, or from mice lacking
post-transcriptional regulation. These modifications have been ZmPSTe24, demonstrate a marked delay in the recruitment of
hypothesized to play a crucial role in the diffusion of DNA p53 binding protein 1 (53BP1) to sites of DNA repair upon
damage response/senescence-associated secretory phenotype exposure to DSB-inducing irradiation (Liu et al., 2005). The delay
(DDR/SAPS) signaling to non-damaged surrounding cells in 53BP1 recruitment to DSBs in these cells and the accumulation
during aging, suggesting that DDR/SASP signaling components of irreparable damage may be a potent physiological genotoxic
may contribute to the development of novel therapeutic stress in individuals with HGPS. Collectively, increased levels of
interventions against age-related diseases (Olivieri et al., 2015). DNA damage may have important consequences in vivo.
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 ANTIOXIDANT AND AGE-RELATED
stimulated in senescent endothelial cells (Prattichizzo et al., DISEASES
2016).
Antioxidants control the autoxidation by interrupting the
propagation of free radicals or by inhibiting the formation of
ACCELERATED-AGING SYNDROMES free radicals via different mechanisms. These compounds help in
scavenging the species that initiate the peroxidation, breaking the
Progerias or accelerated-aging syndromes are partially autoxidative chain reaction, quenching •O− 2 , and preventing the
recapitulated normal aging (Burtner and Kennedy, 2010). formation of peroxides (Gaschler and Stockwell, 2017). The most
Most of the accelerated-aging syndromes are induced by effective antioxidants are those possessing the ability to interfere
modification of nuclear envelope or by defects in DNA repair with the free radical chain reaction. They contain phenolic or
systems. Werner syndrome is the most common accelerated- aromatic rings which allow these antioxidants donate H• to the
aging syndrome derived from DNA repair defects, caused by free radicals formed during oxidation. The radical intermediate
the mutations of Werner syndrome ATP-dependent helicase is then stabilized by the resonance delocalization of the electron
(WRN), a gene coding for a protein implicated in telomere within the aromatic ring (Wojtunik-Kulesza et al., 2016).
maintenance and homology-dependent recombination repair Antioxidant plays a central role in the termination of
(Osorio et al., 2011). Another common accelerated-aging oxidative chain reactions by removing the free radical
syndrome is Hutchinson-Gilford progeria syndrome (HGPS), intermediates (Gholamian-Dehkordi et al., 2017). Many studies
caused by the defects in nuclear envelope proteins due to the indicate that cellular redox status is crucial for ROS-mediated
mutations in the processing protease FACE1/ZMPSTE24 or signaling and mitochondrial function (Fang et al., 2018).
genes encoding lamin A (Worman, 2012). Compared to HGPS, Depletion of intracellular glutathione (GSH) markedly promotes
the onset of Werner syndrome is slightly slower, in which mitochondrial ROS production and triggers mitochondrial
the pathology accompanies with Werner syndrome resembles membrane depolarization (Lohan et al., 2018). Stimulation
a premature aging. Clinical pathology of Werner syndrome of the Nrf2/ARE pathway is fundamental for the induction
starting from 10 to 20 years of age including early graying, short of antioxidant defense enzyme and the modulation of the
stature, hair loss, and bilateral cataracts. The cellular phenotypes intracellular GSH in response to stress (Liu et al., 2018a).
linked to the Werner syndrome demonstrate significant overlap Administration of N-acetylcysteine reverses GSH depletion and
with laminopathies. Further, cells in the absence of WRN have restores ARE-associated transcriptional activity to basal levels
defects in DNA double-strand breaks, especially those bound (Limón-Pacheco et al., 2007). Appropriate intracellular levels
with DNA replication fork arrest. of ROS plays a crucial role in physiological redox signaling
Interestingly, the generation of ROS is increased in HGPS via activation and regulation of endogenous defenses by
fibroblasts (Viteri et al., 2010) and this phenomenon is similar to protecting cells from nitrosative, oxidative, and electrophilic
normal aged fibroblasts. High ROS level in HGPS cells could be stress (Moldogazieva et al., 2018). Indeed, supplementation
attributed to the large DNA damage and subsequently resulting with exogenous antioxidants depletes exercise-triggered
in an underlying defect in early senescence in HGPS cells (Huang improvements in insulin sensitivity and antioxidant gene
et al., 2005; Gonzalez-Suarez et al., 2009). HGPS cells also show expression (Ji et al., 2006), suggesting the importance of
persistent markers of high basal DNA damage, such as nuclear ROS induced endogenous antioxidant enzymes in restoring

physiological redox balance. Additionally, overexpression antioxidants, glutathione is one of the major cellular antioxidant
of thioredoxin (Trx) has been demonstrated to inhibit the (Sifuentes-Franco et al., 2017).
progression of insulin resistance in both type 1 and type 2
diabetes in vivo (Yamamoto et al., 2008). Recent findings Glutathione
suggest that a protective role of Nrf2 on oxidative stress in Glutathione is a pivotal antioxidant present in the
aging (de Oliveira et al., 2018). Depletion of Nrf2 activity has microorganisms, plants, and animals. Glutathione prevents
been identified to contribute to the development of age-related the cell damage induced by ROS including lipid peroxides,
diseases (Cuadrado et al., 2018). peroxides, free radicals, and heavy metals (Pisoschi and Pop,
Several studies as reported by Tan et al. (2018) have shown 2015). Glutathione can scavenge ROS via non-enzymatic
that oxidative stress and obesity-associated non-communicable and enzymatic reactions. The non-enzymatic antioxidant
diseases (NCDs) can be mediated by nutrient-rich in activity is contributed by the free thiol group of glutathione
antioxidants. Indeed, a unique complex of bioactive constituents (Winterbourn, 2016). Additionally, glutathione also detoxifies
can provide protection against oxidative stress, which can cause oxidants and electrophiles via enzymatic reactions which
in inflammation (Tan et al., 2015a,b; Tan and Norhaizan, 2017). involve glutathione reductase, glutathione peroxidase, and
In support of this, numerous epidemiological studies including glutathione-S transferase (Farhat et al., 2018). Glutathione plays
European paradox study (Bellizzi et al., 1994), WHO/MONICA a crucial role in regulating redox state of the cell, specifically via
study (Gey and Puska, 1989), NHS study (Stampfer et al., modulation of the proper tertiary structure of proteins through
1993), and Harvard HPSF (Rimm et al., 1993) have shown that thiol-disulfide exchange concomitantly with glutaredoxin and
antioxidant was negatively associated with many NCDs including protein disulfide isomerases (Ye et al., 2017). Besides antioxidant
cardiovascular diseases. In this regard, the antioxidant capacity properties, glutathione also involves hormones metabolisms
in natural products has drawn attention among scientists in such as estrogens, leukotrienes, and prostaglandins and signal
academia and industry in the prevention of age-related diseases. transduction for transcription (Rotar et al., 2014). Alteration
Figure 2 summarizes the dietary intake of antioxidants in of glutathione concentration has been linked to adverse health
relation to oxidative stress in aging. impacts such as dysregulation of cell proliferation, transcription
Mitochondria-targeted antioxidants have great potential of detoxification enzymes, and apoptosis (Aquilano et al., 2014).
against the damage caused by ROS generation. The ability of Glutathione is categorized as a non-essential nutrient for
mitochondria-targeted antioxidants confers greater protection humans, as it can be synthesized in the body from the amino
against oxidative damage has been attributed to their abilities acids such as L-glutamic acid, L-cysteine, and glycine (Lu S. et al.,
to cross the phospholipid bilayer of mitochondria and thus 2016). The structure of glutathione consists of gamma peptide
eliminating ROS (Oyewole and Birch-Machin, 2015). In bond linked to a tripeptide between the amine group of cysteine
principle, a broad range of antioxidants could be targeted to and carboxyl group of the glutamate side-chain (Figure 3). The
mitochondria via conjugation of triphenylphosphonium (TPP) carboxyl group of cysteine is linked to a glycine by peptide bond
moiety (Smith and Murphy, 2011). In particular, ubiquinol (Gu et al., 2012). The sulfhydryl group of cysteine serves as a
(MitoQ) is the best-characterized antioxidant targeted to proton donor and allows the glutathione to act as an antioxidant
mitochondria by conjugation to the TPP cation (Smith and (Gümüşay et al., 2015). Sulfur is the second chalcogen after
Murphy, 2011). The role of MitoQ will be described in the oxygen in the periodic table with a vacant 3d orbital. The sulfur
ubiquinone section. atom in the sulfhydryl functional group is in its low oxidation
state (García-Santamarina et al., 2014), and thereby sulfhydryl is
strongly susceptible to oxidation even without the presence of the
ROLE OF ANTIOXIDANTS IN THE enzyme.
PREVENTION OF AGE-RELATED Homeostasis of intracellular glutathione is not solely regulated
DISEASES by de novo synthesis, but it also by several factors including
cellular export, utilization, and recycling (Lu S. C. et al., 2016).
Low Molecular Weight Antioxidant This redox cycle is recognized as the glutathione cycle which
Low molecular weight is defined as small molecule biological comprises of glutathione, together with other redox-related
compound (<900 daltons) which regulates body physiological enzymes acts as the first defense against overproduction of
process (Veber et al., 2002; Macielag, 2012). Low molecular harmful ROS in addition to repairing ROS-induced damage
weight antioxidants such as minerals, vitamins, carotenoids, (Schieber and Chandel, 2014). There are three groups of enzymes
cofactors, glutathione, and polyphenols are crucial for involve in the glutathione cycle, namely glutathione reductase,
antioxidative defense mechanisms of cells and organisms glutathione oxidase, and glutathione peroxidase (Reczek and
(Grune et al., 2004). Ascorbic acid (vitamin C) and tocopherol Chandel, 2015). By serving as an electron donor, glutathione
(vitamin E) are the most important low molecular weight reduces disulfide bonds formed between proteins and cytoplasm
antioxidants that cannot be synthesized by a human (Podda and to cysteines. In this process, two molecules of glutathione are
Grundmann-Kollmann, 2001). There are several molecules that converted to an oxidized form, either glutathione oxidase or
are synthesized in the human body and possess an antioxidant glutathione peroxidase. Once oxidized, glutathione reductase
effect including glutathione, lipoic acid, uric acid, taurine, keto is capable to regenerate glutathione from glutathione disulfide
acids, melatonin, coenzyme Q, and melanins. Among these via NADPH-dependent process (Reczek and Chandel, 2015).

FIGURE 2 | The balance of antioxidants and oxidative stress in aging. An inevitable by-product from aerobic respiration, reactive oxygen species (ROS) at the
appropriate level is beneficial and essential for normal cell signaling and cellular immunity. Similarly, reactive nitrogen species (RNS) can be physiologically useful. In a
normally functioning cell, antioxidants may adequately neutralize excess ROS/RNS. However, overproduction of reactive species, including superoxide (O− 2 ), hydroxyl
radical (•OH), peroxynitrite (ONOO− ), hydrogen peroxide (H2 O2 ), hydroperoxides (ROOH), singlet oxygen (1 O2 ), reactive lipid aldehydes, and reactive nitric oxide (NO)
coupled with low level of antioxidants in the body may cause oxidative damage to the cellular constituents (protein, lipids, and DNA). This phenomenon is suffered by
elderly and thereby promoted abnormal cell death, inflammation and subsequently contributes to age-related diseases. Substantial evidence has demonstrated the
importance of antioxidants intake from dietary nutrients to replenish low level of antioxidants (especially endogenous antioxidant such as glutathione and coenzyme
Q10) in the body. Antioxidant plays a pivotal role in scavenging ROS/RNS thus protecting the cells from oxidative damage. Administration of exogenous (minerals,
organosulfur compounds, vitamins, carotenoids, polyphenols) and endogenous antioxidant (antioxidant cofactor such as coenzyme Q10; and low molecular weight
antioxidant: glutathione) have shown to maintain the antioxidant defense and subsequently leads to healthy longevity.
FIGURE 3 | Molecular structures of glutathione, polyphenols (flavonoid, flavonol, flavone, flavanone, anthocyanidin, and isoflavones), and beta-carotene.
Further, glutathione tends to react with cysteine residues in the cells export glutathione disulfide to the extracellular medium
proteins through the formation of mixed disulfides. Yet, these to restore redox imbalance (Heidari et al., 2016). Indeed, the de
unstable molecules can easily be reverted to a normal state by novo synthesis of glutathione is essential for adaptive response
glutathione S-transferase (Carvalho et al., 2016). Alternatively, toward oxidative stress. Many toxic by-products produced from

normal cellular metabolism processes can be detoxified by within the midbrain (Mischley et al., 2015). Removal of ROS
glutathione. A toxic compound, methylglyoxal, generated from by glutathione can facilitate the regulation of redox potential of
the glycolytic process is implicated in ROS production (Chan the midbrain. In a clinical condition, patients with Parkinson’s
et al., 2016). Glutathione detoxifies methylglyoxal by serving as disease were improved following supplementation of reduced
a cofactor of enzyme glyoxalases (Nahar et al., 2015). Besides glutathione (Mischley et al., 2013, 2015).
scavenging ROS, glutathione is also involved in protecting As opposed to the role of the other antioxidants, glutathione
against reactive nitrogen species-mediated damage (Cassia et al., has a complex function in the cancer cells. The level of
2018). NO reacts with the cysteine of glutathione to form S- glutathione was elevated in several human cancer cells such
nitroglutathione (GSNO). GSNO reductase converts GSNO to as colon, bone marrow, breast, and lung cancers. In colon
glutathione disulphide, and subsequently reduces to glutathione cancer cells, the mRNA and protein expressions of glutathione
by glutathione reductase (Cassia et al., 2018). and enzyme involved in the metabolism of glutathione were
The modulation of glutathione metabolism is a useful significantly higher as compared to the normal colonic cell line
adjuvant therapy for many diseases such as cardiovascular (Kim et al., 2015). In support of this, 60% of colon cancer patients
diseases, diabetes, and brain disorders. A study analyzed of expressed high levels of glutathione particularly in tumor tissue
134 cardiovascular disease cases involving 435 individuals (Kim et al., 2015). Similarly, the study reported by Harris et al.
revealed that glutathione can affect the risk of cardiovascular (2015) has also revealed that glutathione is recruited especially
diseases (Shimizu et al., 2004). The data showed that the during cancer initiation. Interestingly, glutathione synthesis is
total plasmic glutathione content is lower in cardiovascular only effective during the early stage of cancer, it is not observed
diseases patients (cerebral infarction and cerebral hemorrhage) in the established tumor (Nguyen et al., 2016). Due to glutathione
compared to healthy subjects (Shimizu et al., 2004). Further, antioxidant activity, there has been a tremendous interest in
glutathione peroxidase was found to be inversely correlated the study of glutathione and its related compounds in diseases
with cardiovascular disease risk (Espinola-Klein et al., 2007). suffered by elderly. The vital role played by glutathione is
Although research has demonstrated a negative association nonetheless worth study in-depth in order to understand the
between glutathione peroxidase and cardiovascular disease risk, pathophysiology pathway underlying in age-related diseases.
not all data demonstrated such a link. Mills et al. (2000) did not
identify an association of glutathione level and atherosclerosis. Polyphenol
Maintaining a normal level of glutathione is important for Polyphenols (also known as polyhydroxyphenols) are
diabetic patients. Diabetes induces an alteration in glutathione characterized by the multiples of phenol structural units
peroxidase and glutathione reductase activity (González de Vega (Nascimento-Souza et al., 2018). The numbers and characteristics
et al., 2016). Intake of glutathione in patients with type 2 of these phenol structures contribute to the unique features of
diabetes mellitus increase the platelet constitutive nitric oxide polyphenol compound in term of chemical, physical, and
synthase activity and reduce plasminogen activator inhibitor-1 biological (Scalbert and Williamson, 2000). In brief, polyphenols
(PAI-1; Martina et al., 2001). PAI-1 is an inhibitor of fibrinolysis are secondary metabolites (Kabera et al., 2014) produced by
which increases the risk of thrombosis (Tofler et al., 2016). plants, which is widely found in fruits and vegetables are thought
This study indicates that glutathione may play a vital role in to protect against ultraviolet radiation (Zbikowska et al., 2016)
the pathophysiology of diabetes. Further, nephropathy is a life- and pathogens invasion (Nagpala et al., 2016). Polyphenols also
threatening complication suffered by both Type 1 and Type 2 affect the flavor, color, and odor which contribute to the sensory
diabetes patients (Hadjadj et al., 2016). Diabetic nephropathy perception of the food (Ju et al., 2017). Of all polyphenolic
is often linked to low renal glutathione levels. Dietary compounds, the flavonoid is the most common polyphenol
supplementation with glutathione has been demonstrated to classes (Nascimento-Souza et al., 2018).
protect against pathologies associated with diabetic nephropathy Flavonoids are comprised of the most studied group of
(Lash, 2015). polyphenol. The basic structure of flavonoid is a diphenylpropane
In the brain, glutathione is only presented in millimolar skeleton, which composed of two benzene rings (rings A and
concentrations, and thus makes this organ prone to oxidative B) connected by three-carbon chains that form a closed pyran
damage compared to other tissues in the body (Settineri et al., ring (heterocyclic ring containing oxygen, ring C; Das et al.,
2018). A disruption in glutathione homeostasis could induce 2017). The structure of flavonoids is denoted as C6-C3-C6
oxidative stress and lead to neurodegenerative diseases including (Das et al., 2017). Generally, B ring is bonded to position 2
Parkinson’s disease (Mischley et al., 2013), Alzheimer’s disease of C ring, but some of them are attached at position 3/4.
(Braidy et al., 2015), and dementia (Duffy et al., 2015) which Flavonoids are subdivided into different subgroups (flavonols,
impaired motor and cognitive functions. Parkinson’s disease is flavones, flavanonols, flavanones, catechins, anthocyanins, and
a dopamine deficiency condition resulted from the destruction chalcones; Figure 3) based on the carbon and the degree of
of dopaminergic neurons in the midbrain region (Zucca et al., unsaturation (Gonzales et al., 2015). The physiological function
2017). ROS is generated during dopamine normal metabolism of the flavonoids is depends on the structural characteristics as
(Guo et al., 2018). The decline of glutathione levels in Alzheimer’s well as the pattern of glycosylation and hydroxylation of the three
patient was associated with downregulation of glutathione rings (Gonzales et al., 2015).
homeostasis (Braidy et al., 2015). Parkinson’s patients suffer There are around 6,000 flavonoids that form the colorful
depletion of glutathione levels coupled with an increase of ROS pigments of herbs, fruits, vegetables, and medicinal plants.

Flavonoids are known for its broad spectrum of health- via modulation of vasodilation. Isoflavone improves brachial
promoting effects on human and animal (Panche et al., artery flow through interaction with the estrogen-response
2016). The antioxidative, antimutagenic, anti-inflammatory, element of genes related to endothelial NO synthase (Ramdath
and anticarcinogenic properties coupled with their abilities to et al., 2017). Compared to those who consume placebo,
regulate key cellular enzyme function have drawn attention supplementation of isoflavone in postmenopausal women for
from the pharmaceutical industry, which attempts to design the 6 months improved endothelial vasodilation and lowered
prevention and treatment of certain diseases (Panche et al., 2016). the cellular adhesion molecules such as E-selectin, ICAM-
The antioxidant activities of flavonoids include (1) scavenging 1, and vascular cell adhesion protein 1 (Colacurci et al.,
ROS (Shokoohinia et al., 2015); (2) suppressing generation of 2005). A recent study by Grosso et al. (2017) showed that
ROS by inhibition of enzymes (Nile et al., 2016) and chelating intakes of dietary flavonoids (flavonols, flavones, flavanones,
trace elements (Catapano et al., 2017); and (3) upregulating anthocyanidins, and proanthocyanidins) are associated with
antioxidant defenses. The low redox potential of flavonoids decreased risk of cardiovascular disease mortality. These
enables the reduction of highly oxidized free radicals such as data suggest that dietary flavonoids as natural cardiovascular
superoxide, alkoxyl, hydroxyl, and peroxyl radicals by proton protectors.
donation (Kovacic and Somanathan, 2011). Flavonoids inhibit Diabetes mellitus is suffered by elderly and can lead to
the enzymes such as xanthine oxidase (Nile et al., 2016) severe complication such as diabetic peripheral neuropathy.
and protein kinase C (Maurya and Vinayak, 2015) which are A study reported by Ganugapati et al. (2011) showed that
responsible for the generation of superoxide anion. Flavonoids green tea flavonoids and epicatechin activate the insulin
have also been reported to inhibit other ROS generating enzymes receptor and reduce the harmful effects of diabetes. Grape seed
including COX, microsomal monooxygenase, lipoxygenase, proanthocyanidin alleviates type 2 diabetes mellitus in the rat
mitochondrial succinoxidase, and NADH oxidase (Pietta, 2000). through ameliorating of hyperglycemia and increases Ca2+ -
Therefore, the ability of flavonoids in chelating trace metals plays ATPase activity in sciatic nerve (Ding et al., 2014). Quercetin
an important role in the oxygen metabolism (Catapano et al., is another bioflavonoid available in red wine and many plants.
2017). Intake of quercetin was shown a neuroprotective effect in the
Flavonoids have beneficial biochemical and antioxidant effects diabetic rats against high glucose-induced injury on the glia and
in relation to several oxidative stress-induced diseases in myenteric neurons at the cecum. The neuroprotective effects
elderly for instance cancer (Chien et al., 2015), diabetic (Ding could be attributed to NF-κB inhibition and nuclear factor
et al., 2014), cardiovascular diseases (Roohbakhsh et al., 2015), E2-related factor 2/heme oxygenase-1 (Nrf-2/HO-1) activation
Alzheimer’s disease (Swinton et al., 2018), and dementia (Swinton (Sandireddy et al., 2016). In another study, Kwak et al. (2017)
et al., 2018). Several flavonoids such as naringin (Ahmad revealed that baicalein, a flavonoid found in traditional Chinese
et al., 2015), apigenin (Erdogan et al., 2016), and isorhamnetin herbal medicine can inhibit the oxidative-nitrosative stress and
(Manu et al., 2015) have been demonstrated to reduce the p38 MAPK activation and subsequently lead to alleviation of
inflammatory mediators production via the blockade of NF-κB diabetic peripheral neuropathy.
pathway. Flavonoids were found to negatively correlate with Many studies revealed that flavonoids from cocoa (Swinton
several types of cancer in human based on numerous studies. et al., 2018), green tea (Swinton et al., 2018), and citrus
In woman aged 75 years old and above, high total flavonoids fruit (Braidy et al., 2017) exert beneficial effects to the brain.
intake reduced the risk of cancer mortality compared to those Emerging evidence has suggested that flavonoids protect against
with low total flavonoids consumption (Ivey et al., 2015). A neural injuries and degeneration in Alzheimer’s disease and
decrease in breast cancer risk among postmenopausal women dementia. In the brain, flavonoids act as a potent antioxidant,
was found to be associated with flavonoids intake specifically, anti-inflammatory, anti-apoptotic and signaling pathways
flavan-3-ols, flavones, flavonols, and lignans (Fink et al., 2006). modulatory agents via interactions with the ERK and PI3-
While for colorectal cancer, He and Sun (2016) found that 2 kinase/Akt signaling pathways (Jiang et al., 2016). Further,
flavonoid subclasses, namely procyanidins and isoflavones exert increased cerebral brain blood flow by flavonoids may also
preventive effects toward the risk of colorectal cancer. However, enhance cognition (Grassi et al., 2016). In addition, flavonoids
there was limited evidence of the lower risk of colorectal cancer have also been reported to slow down the development
via flavonoid consumption (He and Sun, 2016; Grosso et al., 2017; of Alzheimer’s disease-like pathophysiology and related
Zamora-Ros et al., 2017). neurodegenerative disorders through disrupting amyloid β
Many studies demonstrated that a flavonoid-rich diet is protein production, activating of α-secretase (ADAM10),
related to a lower risk of cardiovascular disease. Flavonoids and inhibiting of β-secretase (BACE-1) (Folch et al., 2018).
prevent cardiovascular disease via a few mechanisms such Together, the evidence showed that flavonoids have outstanding
as antioxidant, anti-inflammatory, antiplatelet, and increasing potential to block the initiation and progression of age-related
high-density lipoprotein (HDL) level (Nunes et al., 2016). A diseases and pathologies. High intake of flavonoids should
study found that the intake of soy isoflavone reduces the risk be included in the dietary of elderly via supplementation or
of cardiovascular disease due to chronic inflammation. This flavonoid-rich containing food. Table 1 summarizes some
favorable effect could be attributed to the downregulation of the of the clinical trials of antioxidants in preventing age-
TNF-α at the endothelial level (Nadadur et al., 2016). Studies related diseases and the failure of clinical trials involving
have shown the ability of isoflavone to alleviate hypertension antioxidants.

TABLE 1 | Clinical studies conducted in several antioxidants and their effects in age-related diseases.
Antioxidants Age-related diseases Findings References
Glutathione Atherosclerosis No effect Mills et al., 2000

Cardiovascular disease Total plasmic glutathione content is lower in cardiovascular Shimizu et al., 2004
diseases patients (cerebral infarction and cerebral
hemorrhage) compared to healthy subjects
Cardiovascular disease risk Espinola-Klein et al., 2007
Type 2 diabetes mellitus Platelet constitutive nitric oxide synthase activity and reduce Martina et al., 2001; Lash, 2015
plasminogen activator inhibitor-1 (PAI-1)
Protect against pathologies associated with diabetic
nephropathy
Alzheimer’s patient Glutathione levels in Alzheimer’s patient were associated Braidy et al., 2015
with downregulation of glutathione homeostasis
Parkinson’s disease Free radicals involved in neurological complications Mischley et al., 2015
Cancer 60% of colon cancer patients expressed high levels of Kim et al., 2015
glutathione particularly in tumor tissue
Polyphenols Cancer Risk of colorectal cancer Grosso et al., 2017; Zamora-Ros
et al., 2017
Cardiovascular disease Risk of cardiovascular disease mortality Grosso et al., 2017
Vascular endothelial dysfunction and regulating lipid Rasines-Perea and Teissedre, 2017
metabolism
Diabetes Improve glucose control and insulin sensitivity Vitale et al., 2018
Carotenoids Alzheimer’s disease and dementia Risk of Alzheimer’s disease mortality and dementia Min and Min, 2014; Feart et al., 2015
Rheumatoid Mortality rate Bjelakovic et al., 2012
Cardiovascular disease Risk in stroke, coronary artery disease, and cardiovascular Leermakers et al., 2016;
disease Valderas-Martinez et al., 2016
Inversely correlated with oxidized LDL Nakazato et al., 2014
Mortality rate Bjelakovic et al., 2012; Kishimoto
et al., 2017
Hypertension Baseline blood pressure Perrone et al., 2016
Age-related macular degeneration Risk in individuals who consume a carotenoid-rich diet Eisenhauer et al., 2017
Osteoporosis Bone density and fracture risk Rao and Rao, 2015; Hayhoe et al.,
2017
Hip fracture risk by 28% Xu et al., 2017
Cancer Lycopene intake can prevent prostate cancer Zu et al., 2014
The incidence of lung cancer in the treatment group (30 mg Omenn et al., 1994
of beta-carotene and 25,000 IU of retinol daily) in the smokers
and workers in asbestos mines compared to the placebo
group
The incidence of lung cancer in male smokers (50–69 years) Blumberg and Block, 1994
who received beta-carotene
Zinc Type 2 diabetes mellitus Plasma thiobarbituric acid reactive substances Anderson et al., 2001
Improved insulin sensitivity Vashum et al., 2014
Age-related macular degeneration Delay the development of age-related macular degeneration Group, 2001; Gorusupudi et al., 2017
and vision loss in individuals older than 55 years
Low intake of zinc was associated with age-related macular Aoki et al., 2016
degeneration
Ascorbic acid Diabetes mellitus and coronary artery Forearm vasodilator response Antoniades et al., 2004
disease
Cardiovascular disease Cardiovascular disease Wang et al., 2013
Supplementation with a dosage >500 mg/d shows a better Ashor et al., 2014
endothelial function
Endothelial dysfunction and improve lipid profile Moser and Chun, 2016
Age-related neurodegenerative Ascorbate shortage may contribute to the dysregulation of 5 Al-Mahdawi et al., 2014
diseases hmC
Cancer Exert antitumor activity Ma Y. et al., 2014; Yun et al., 2015
(Continued)

TABLE 1 | Continued
Antioxidants Age-related diseases Findings References
Tocopherols and Cancer No effect Lonn et al., 2005

tocotrienols
Alzheimer’s disease Lipid peroxidation by up to 60% compared with that of the Morris et al., 2005
control
Positively associated with perceptual speed Hensley et al., 2011
Stimulate phosphoprotein phosphatase 2A (PP2A) Voronkov et al., 2011
Cardiovascular disease Cardiovascular mortality risk Schwingshackl et al., 2017
No effect Lonn et al., 2005
Myocardial infarction Chronic heart failure in patients with left ventricular Marchioli et al., 2006
dysfunction
Vascular disease Risk of heart failure Wannamethee et al., 2013
Osteoporosis Positive relationship between bone mineral density and Shi et al., 2016
α-tocopherol level in an elderly Chinese population
Ubiquinone Parkinson’s disease Slow down the functional decline experienced by early-stage Shults et al., 2002
of Parkinson’s disease patients
Cellular pathophysiological alterations linked to a Cooper et al., 2012
mitochondrial dysfunction in Parkinson’s disease patients
No effect Snow et al., 2010
Type 2 diabetes mellitus Enhances nerve conduction parameters of diabetic Hernández-Ojeda et al., 2012
polyneuropathy and ameliorates oxidative stress
Nitric oxide production in patients received 200 mg Watts et al., 2002
CoQ10/day for 12 weeks
Increases insulin sensitivity and improves beta cell function in Raygan et al., 2016
diabetic patients
Improve vascular dysfunction and decrease the glycemic Mantle, 2017
response
Coronary artery disease Antioxidant enzymes activities and inflammation Lee et al., 2013
Congestive heart failure Improve the quality of life in patients Oleck and Ventura, 2016
Risk of mortality Lei and Liu, 2017
Sulfur compounds Type 2 diabetes mellitus Improve glucose control Sobenin et al., 2008
No hypoglycemic effects Afkhami-Ardekani et al., 2006
Carotenoids Most carotenoids are tetraterpenoids, derive from 8 isoprene

Carotenoids are naturally occurring organic pigments that are molecules and contain 40 carbon atoms (Harrison and Curley,
produced in the plastids of plants and algae, several bacteria, and 2016). All carotenoids have polyisoprenoid structure comprised
fungi (Alós et al., 2016). The only animals known to produce of a long-conjugated chain adjacent toward the multiple double
carotenoids are spider mite (Tetranychus urticae) and the red bonds with near symmetry on the central double bond. This basic
pea aphid (Acyrthosiphon pisum), which have acquired the ability acyclic structure can be altered by oxygen-rich functional groups
to synthesize the carotenoids from fungi via gene transfer (Du (Gabriel et al., 2015). The electron-rich conjugated system of
et al., 2017). In general, carotenoids absorb wavelengths between the polyene structure allows the carotenoids function as efficient
400 and 550 nanometers, thus the compounds appear in yellow, radical scavengers by quenching the singlet oxygen and trapping
orange, or red color (Gauger et al., 2015). peroxyl radicals (Nishino et al., 2016).
Currently, there are more than 600 carotenoids that Carotenoids are not only exerted antioxidant properties, they
have been discovered to perform a range of functions are also facilitated in the modulation of cell cycle, apoptosis,
(Paliwal et al., 2016). Carotenoids are divided into two and cell differentiation (Gloria et al., 2014), enhancement of
classes, namely carotenes and xanthophylls based on their immune system (Karadas et al., 2016), regulate of cell signaling
chemistry constitute (Yaroshevich et al., 2015). Hydrocarbon- pathways (Kim et al., 2016), promote growth factors (Diener
only carotenoids (α-carotene, β-carotene, and lycopene) are and Rohrmann, 2016), and adhesion molecules (Llorente et al.,
known as carotenes (Figure 3); whereas oxygenated derivatives 2017). Carotenoids are highly lipophilic molecules that reside
are called xanthophylls. On the other hands, oxygen substituents intracellularly to shield the membrane from oxidative stress
(lutein and zeaxanthin), keto/oxo groups (echinenone and (Fiedor and Burda, 2014). Carotenoids are well-recognized as
canthaxanthin), epoxide groups (violaxanthin, antheraxanthin, an eye-sight protecting agent. Such carotenoids are classified
and neoxanthin), and aldehyde groups (β-citraurin) are classified as pro-vitamin A which contains unsubstituted β-ionone ring
as complex xanthophylls (Berman et al., 2015). (α-carotene, β-cryptoxanthin, β-carotene, and γ-carotene) and

can be converted into retinal (Sandmann, 2015). Vitamin A of carcinogenesis via its anti-inflammatory actions (Carini et al.,
deficiency affects immunity and subsequently leads to the damage 2017). A follow-up study conducted from 1986 to 2010 involving
of light-sensitive receptors (Gonçalves et al., 2016). Individual 49,898 of males revealed that higher lycopene intake can prevent
with vitamin A deficiency may acquire a permanent blindness prostate cancer (Zu et al., 2014). The preventive role of lycopene
known as xerophthalmia (West, 2015). Carotenoids such as toward cancer is more likely due to its antioxidant effect. Yet,
lutein and zeaxanthin which is localized in the eye macula the anticancer ability of lycopene is mediated through several
may protect against harmful blue and near-ultraviolet light mechanisms including modulation of cell cycle arrest, apoptosis,
(Ma et al., 2016). Age-related macular degeneration (AMD) is growth factor signaling, and phase II detoxifying enzymes
the main cause of blindness suffered by people aged 75 years (Aizawa et al., 2016). However, several studies demonstrated that
and above in developed countries. AMD accounts for nearly smokers or workers in asbestos mines who received β-carotene or
8.7% of all blindness worldwide (Wong et al., 2014). Research α-tocopherol alone is susceptible to lung cancer compared to the
findings have predicted that the percentage of patients with placebo group (Blumberg and Block, 1994; Omenn et al., 1994).
AMD tends to double between 2010 and 2050 (Eisenhauer et al., Bone loss in the elderly leads to osteoporosis. Studies in
2017). Oxidative stress within the retina has been implicated in both human and animal models have suggested that carotenoids
the pathogenesis of AMD. Compared to the other cells, non- could reduce the risk of osteoporosis (Rao and Rao, 2015).
proliferative postmitotic cells such as photoreceptors and retinal Carotenoids have shown a positive impact on bone cells. For
pigment epithelium cells are extremely sensitive to oxidative instance, β-carotene was significantly inhibited the bone marrow-
damage due to the absence of DNA damage detection systems derived macrophages viability (Wang et al., 2017). Beta-carotene
(Blasiak et al., 2014). Further, the macular environment can decreased the receptor activator of nuclear factor kappa B ligand
also stimulate ROS generation. The macula is continuously (RANKL)-induced osteoclastogenesis via inhibition of NF-κB
exposed to high oxidative stress from the high partial pressure pathway (Wang et al., 2017). Other carotenoids such as β-
of choriocapillaris and oxidized polyunsaturated fatty acids cryptoxanthin, α-carotene, lutein, and lycopene also facilitate
(PUFAs) of the retinal outer segments (Schmidt-Erfurth, 2005). the alleviation of bone loss. A meta-analysis involving 140,265
Compared to those who never or rarely consume carotenoids, participants and 4,324 cases suggested that high dietary intake of
individuals who consume a carotenoid-rich diet have a relatively total carotenoids reduced the hip fracture risk by 28% (Xu et al.,
low risk of age-related macular degeneration (Eisenhauer et al., 2017). Another study conducted by Hayhoe et al. (2017) also
2017). showed that bone density and fracture risk is inversely correlated
In addition to the oxidants scavenging ability, lutein also with dietary intake of carotenoids.
inhibits the activation of NF-κB which plays a significant role Carotenoids have been demonstrated to prevent many
in the pathogenesis of various human diseases. NF-κB enters degenerative diseases induced by an oxidative stress such as
the nucleus, downregulates the inducible gene transcription and Alzheimer’s disease and dementia (Mohammadzadeh Honarvar
triggers the production of inflammatory markers such as iNOS, et al., 2017). The implication of carotenoids toward the
chemokines, and cytokines (Serasanambati and Chilakapati, pathophysiology of Alzheimer’s disease and dementia has been
2016). The antioxidant and anti-inflammatory properties of extensively studied in both in vitro and in vivo models (Masisi
lutein are not limited to only eyes but it also decreases the et al., 2016). Carotenoids delay disease progression via multiple
risk of cardiovascular diseases (Maria et al., 2015), coronary pathways such as suppress oxidative stress (Wang et al., 2018),
artery disease (Nakazato et al., 2014), and cancers (Rafi et al., promote Aβ peptide production (Lin et al., 2017), and inhibit
2015) in older people. Previous studies have demonstrated that pro-inflammatory cytokines (Hadad and Levy, 2017). Beta-
intake of lutein was inversely correlated with oxidized LDL, carotene is an Alzheimer’s disease antagonist due to its high
suggesting that lutein may protect against the development of binding energy toward Alzheimer’s disease-related receptors (P53
atherosclerosis (Kishimoto et al., 2017). Increased plasma lutein kinase receptor and histone deacetylase; Krishnaraj et al., 2016).
levels also decrease baseline blood pressure, which subsequently A marine carotenoid, fucoxanthin suppresses Aβ formation and
reduces the risk of hypertension (Perrone et al., 2016). The destabilizes Aβ fibril (Xiang et al., 2017). A study reported by
data from the previous study further demonstrated that lutein Ono and Yamada (2012) further revealed that both vitamin A
shields the myocardium from ischemia injury by reducing and β-carotene can block the oligomerization of Aβ40 and Aβ42
apoptosis and oxidative stress (Maria et al., 2015). A meta- during Aβ peptide formation. Another carotenoid, lycopene
analysis conducted by Leermakers et al. (2016) showed that high was shown to reduce the Aβ42-induced inflammatory cytokine
dietary intake of lutein is negatively linked to stroke and coronary such as IL-1β, NF-κB, transforming growth factor beta (TGF-
heart disease. However, Bjelakovic et al. (2012) reported that β- β), and TNF-α in the brain (Sachdeva and Chopra, 2015).
carotene increases the mortality rate of cardiovascular disease Data from the human studies revealed that higher plasma
and rheumatoid. levels of lutein reduced the risk of Alzheimer’s disease and
Lutein not only reduces cardiovascular disease but it also dementia (Feart et al., 2015). High level of carotenoids (lutein,
inhibits age-related cancers such as breast cancer via modulation zeaxanthin, and lycopene) in serum has also been associated
of NrF2/ARE and NF-κB pathways (Chang et al., 2018). Another with a lower risk of Alzheimer’s disease mortality (Min and Min,
common carotenoid, lycopene is widely accepted as a potent 2014).
antioxidant and reduces the risk of certain cancers such as The health-promoting values of carotenoids revealed the
lung (Aizawa et al., 2016), prostate (Graff et al., 2016), colon link between carotenoid-rich diets and age-related illnesses. The
(Huang R. F. et al., 2015). Lycopene suppresses the progression intake of raw tomato (Solanum lycopersicum) shields against

cancers (esophagus, stomach, colon, and rectum) (Berman et al., as a cofactor in enzymes such as retinol dehydrogenase, an
2015), cardiovascular diseases (Valderas-Martinez et al., 2016), enzyme for vitamin A cycle. Several studies have reported the
as well as Alzheimer’s disease (Oboh et al., 2015). Based on importance of dietary zinc and age-related macular degeneration.
the evidence, dietary intakes of certain antioxidants such as A human study involving 369 participants revealed that a
carotenoids can reduce the risk of age-related diseases. The effects low intake of zinc was associated with age-related macular
of multiple carotenoids in diet offer healthy aging in term of degeneration (Aoki et al., 2016). A follow-up study for 6
nutrition. years including 3,640 participants had revealed a significant
role of zinc in age-related macular degeneration (Group,
Dietary Minerals 2001). It has been shown that for individuals older than 55
Minerals are naturally occurring elements with universal years, zinc supplements may delay the development of age-
structures and definite chemical formulas. Dietary minerals related macular degeneration and vision loss (Group, 2001).
are the chemical substances required by all living organisms. Similarly, a meta-analysis of 23,099 individuals demonstrated
Adequate intake of each dietary mineral is essential to maintain that dietary zinc blocks the progression of age-related macular
physical health. Minerals play a crucial role in bone formation, degeneration and delay its progression (Gorusupudi et al.,
hormones synthesis, regulation of heartbeat and others (Morris- 2017).
Naumann and Wark, 2015). Most of the minerals in human In addition to the effects mentioned above, zinc
diet come from food and drinking water. Mineral supplements supplementation has been reported to suppress the oxidative
are made available in the market for those who did not meet stress in type 2 diabetes via several mechanisms. These favorable
the daily dietary intake of mineral (Schwalfenberg and Genuis, effects could be attributed to the activity of zinc which is involved
2015). in the insulin production, secretion, and action processes by
Dietary minerals are categorized into two different groups, acting as a catalytic cofactor for carboxypeptidase H enzyme.
which are macrominerals and trace minerals. Macrominerals Carboxypeptidase H enzyme is responsible for the conversion
including phosphorus, calcium, sodium, magnesium, potassium, of proinsulin (inactive form) into insulin (active form). Further,
and chloride in which the body needs in larger amounts. By zinc also facilitates the phosphorylation of the insulin receptor
contrast, trace elements are dietary minerals that are required by transporting more glucose into the cells. In human studies,
in minimal amounts for regular cellular function, such as a significant decrease in plasma thiobarbituric acid reactive
copper, selenium, zinc, iodine, fluoride, and iron (Siddiqui et al., substances, an oxidative stress indicator was found in patients
2014). Most of these trace elements are the functional part with type 2 diabetes supplemented with zinc (Anderson et al.,
of enzymes. Yet, intakes of a large amount of trace elements 2001). Zinc also improved insulin sensitivity and subsequently
are noxious to both human and animals (Mikulewicz et al., reduces the chronic hyperglycemia in type 2 diabetes mellitus
2017). For instance, trivalent chromium is responsible for glucose (Vashum et al., 2014). Overall, zinc plays a significant role as an
metabolism by acting as a cofactor for insulin action. However, antioxidant nutrient that regulates metabolic control in type 2
massive inhalation of hexavalent chromium, a toxic industrial diabetes mellitus pathophysiology.
pollutant is carcinogenic to both animals and human. Chromium Notably, data from epidemiologic studies found that dietary
exposure has been associated with various cancers in lung, central zinc intake may reduce the risk of cancer (Costello and
nervous system, and gastrointestinal tract (Bhattacharya et al., Franklin, 2016). Zinc suppresses the proliferation of cancerous
2016). cells via several mechanisms. In cancer cells, zinc inhibits
Minerals such as copper, magnesium, zinc, and selenium mitochondrial terminal oxidation and respiration and stimulates
possess antioxidant properties. Zinc functions as an antioxidant apoptogenesis of mitochondria (Costello and Franklin, 2016).
in the body via regulation of glutathione metabolism (Stelmach Further, zinc also prevents the migration of malignant cells
et al., 2014), inhibition of nicotinamide adenine dinucleotide through activation of intracellular signaling pathways. In prostate
phosphate-oxidase (NADPH-oxidase) enzyme (Marreiro et al., cancer cells, zinc is accumulated in the expression of the zinc
2017), modulation of metallothionein expression (Alvarez et al., uptake transporter, ZIP1 (Franklin and Costello, 2007). The
2016), and serves as a cofactor for superoxide dismutase enzyme accumulated zinc exerts its antiproliferative activity toward the
(Marklund et al., 1982). prostate cancer cells via activation of MAPKs and inhibition
The non-enzymatic antioxidants taking part in the first line the growth of cancer cells (Beyersmann and Haase, 2001). In
of defense belong to preventive antioxidants. These antioxidants colorectal cancer, zinc was found to activate Raf-1-MEK-MAPK
inhibit the formation of new reactive species by interacting with kinases followed by the activation of Elk-1 dependent trans-
the transition metal ions (Mironczuk-Chodakowska et al., 2018). reporter gene expression (Park et al., 2002). The downregulation
Non-enzymatic antioxidants are not only involved in the first line of cancer cell growth by zinc indicates that the therapeutic
of defense, it also involved in the second line of defense against potential of zinc to regulate the growth of cancers. Taken
ROS that is represented by molecules characterized by the ability together, minerals are a good antioxidant which is best supplied
to inactivate oxidants and radicals (Mironczuk-Chodakowska by ingesting specific foods rich with that chemical element
et al., 2018). of interest. The beneficial effect of mineral on aging is
Abundance level of zinc can be found in the retina which worth attention. However, an overdose of mineral intake is
implicated the antioxidant defense systems of the eye (Ugarte not recommended and may cause a detrimental impact on
et al., 2014). Zinc carries out its antioxidant functions and serves health.

Ascorbic Acid acid and anticancer activity require further elucidation, most of
Ascorbic acid, also known as vitamin C, is one of the the experimental studies indicate that modulating oxidative stress
most ubiquitous hydrosoluble antioxidants. In physiological could play a crucial role (Badgujar et al., 2015; Huang et al., 2017).
pH conditions, vitamin C exists mainly as an ascorbate anion In this regard, a key mode of action to explain this relationship is
(Camarena and Wang, 2016). Ascorbic acid has 4 –OH groups via glucose transporter type 1 (GLUT1) which increases uptake
(Figure 4) that can donate hydrogen to an oxidizing system. of the oxidized form of ascorbic acid, dehydroascorbate and
Due to the –OH groups (2 pairs of 2) are on adjacent toward subsequently depletes glutathione (Yun et al., 2015).
the carbon atoms, ascorbic acid is susceptible to chelate metal Compared to those who rarely or deficient in ascorbic
ions (Fe++ ). Ascorbic acid serves as a reducing agent, scavenge acid, adults who supplemented with ascorbic acid is negatively
free radicals, and quench •O− 2 . At high levels of ascorbic acid associated with adiposity (Hosseini et al., 2017). Several studies
(>1,000 mg/kg), it tends to shift the balance between ferric iron have corroborated this finding and found that ascorbic acid
(Fe3+ ) and ferrous (Fe2+ ) and thereby scavenge the oxygen and suppressed leptin stimulation from adipocytes, particularly in
inhibit oxidation (Brewer, 2011). Ascorbic acid is a cofactor insulin-secreted cells (Garcia-Diaz et al., 2010). Reduction in
for many enzyme-catalyzed reactions such as maintaining of leptin may trigger a significant reduction in hypertension (Lane
connective and vascular tissue’s integrity, enhancing the collagen and Vesely, 2013). Intriguingly, leptin deficiency is linked to the
biosynthesis and iron absorption, modulating the leukocyte and early-onset of obesity, indicating that ratio of leptin to insulin
hematopoiesis functioning, neuroprotection, and hydroxylation is fundamental in the homeostatic balance of fat and glucose
of lysine and proline (May and Harrison, 2013; Spector and metabolism (Wabitsch et al., 2015).
Johanson, 2014). Data from a meta-analysis included a study from inception to
Data from both animal and population-based studies have May 2013 demonstrated that an ascorbic acid supplementation
shown that a correlation between the process of aging and with a dosage > 500 mg/d shows a better endothelial function
reducing ascorbate levels in tissues (Michels and Hagen, 2004; (Ashor et al., 2014). In a further study focused on cardiovascular
Dixit et al., 2015). The mechanisms that implicate the declining disease outcomes, Wang et al. (2013) showed that high ascorbic
of age-related ascorbate are complex and involve multiple cell acid intake is negatively linked to cardiovascular disease. In
signaling pathways such as accelerated turnover, increased usage, another meta-analysis of randomized controlled trials, Ashor
reduced cellular uptake, and decreased absorption/reabsorption. et al. (2014) found that a relatively low risk for incidence of
For instance, ascorbate level reduces for nearly 50% in leukocytes cardiovascular disease for those with a greater intake of ascorbic
in individuals at age 85 and above compared to those at acid supplements. Importantly, cellular adhesion molecules are
age 60 (Attwood et al., 1978). Despite the limited available biochemical markers of endothelial dysfunction concomitantly
evidence on ascorbate level in human brains, the previous with inflammation. Ascorbic acid was effective by neutralizing
study has reported that ascorbate level in the cerebral cortex the oxidized-low density lipoprotein (oxLDL) activity, which
is declined for nearly 77% from an individual at age 80 and is known as the trigger of the initiator of atherosclerosis and
older, compared to that individual at age 50 and younger inflammatory process in the endothelial tissue (Ellulu, 2017).
(Schaus, 1957). A study reported by Al-Mahdawi et al. (2014) Notably, some research has emerged to suggest that ascorbic acid
has shown that ascorbate shortage may contribute to the improved endothelial function in diabetic patients (Ashor et al.,
dysregulation of 5hmC, which subsequently contributes to the 2014). The previous study stated that patients with diabetes had
age-related neurodegenerative diseases. Research evidence has relatively low amounts of circulating ascorbic acid concentrations
demonstrated the potential protective function of ascorbate in or known as latent scurvy (Price et al., 1996). Taken together,
neurodegenerative diseases (Barnham et al., 2004; Ruszkiewicz ascorbic acid may be a useful nutritional intervention for the
and Albrecht, 2015). Ascorbate supplementation markedly secondary prevention of age-related diseases.
improves the differentiation of midbrain derived neural stem
cell against dopaminergic neurons, which is associated with Vitamin E
the TET-mediated 5hmC generation and Jmjd3 catalyzed loss Vitamin E consists a group of eight structurally associated
of H3K27m3 (He et al., 2015). In this regard, these findings lipophilic chromanol congeners. Vitamin E usually found
imply that ascorbate plays a critical role in dopaminergic neuron naturally in food including four tocopherols and four
differentiation (Camarena and Wang, 2016). tocotrienols, all of which possess saturated and three double
In addition to the effects mentioned above, ascorbic acid bonds in their phytyl tails, respectively. Both tocopherols and
has the potential to protect against cancers. High concentration tocotrienols are further classified into α-, β-, γ-, and δ- based
of ascorbic acid induces cytotoxicity against cancer cells in on the methyl and hydroxyl substitution in their phenolic rings
vitro (Vuyyuri et al., 2013; Tian et al., 2014) and delays tumor (Figure 4) (Joshi and Pratic, 2012). Among all isoforms of
growth in xenograft models (Kim et al., 2012; Ma Y. et al., vitamin E, α-tocopherol is predominantly found in mammalian
2014). The animal model study further demonstrated that feeding tissue; conversely, γ-tocopherol is the primary form of vitamin
Apc/KrasG12D mutant mice high-dose ascorbic acid may impair E in the diet and exerts potent antioxidant property (Joshi and
tumor growth (Yun et al., 2015). Consistent with the data Pratic, 2012).
reported by Yun et al. (2015) and Ma Y. et al. (2014), Wu The activity of several protein kinases, and particularly of
et al. (2017) identify an antitumor activity of ascorbic acid in a protein kinase C (PKC) sub-family members can be modulated
clinical study. Although the molecular link underlying ascorbic in human neuronal cells supplemented with tocopherols and

FIGURE 4 | Molecular structures of ascorbic acid and vitamin E congeners including tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol) and
tocotrienols (α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol).
tocotrienols (Galli et al., 2017). This signaling influences tocopherols and tocotrienols may induce therapeutic effects via
apoptotic cell death and cell cycle regulation in different cell modulation of enzymatic and non-enzymatic pathways to reduce
line models such as human neurons and glioblastoma cells with the impairment of neurological function.
a strong effect of α- and γ-tocopherol on the phosphorylative Besides its effects on neuroinflammation, previous studies
stimulation of pro-survival MAPK-ERK isoforms. In a close have demonstrated the role of this vitamin as a factor essential
similarity with the results obtained for α-tocotrienols in the post- for other crucial functions and the development of organs
ischemic brain (Park et al., 2011), α-tocotrienols protect mouse and tissues for example bones, demonstrating the enormous
hippocampal and cortical neurons from cell death via modulation functional potential of tocopherols and tocotrienols. In the
of neurodegenerative signaling cascades, and thereby preserve context of osteoporosis, tocotrienols therapy has provided
the function of that brain area (Ambrogini et al., 2014). A study significant beneficial outcomes. Gamma-tocotrienol significantly
by Khanna et al. (2010) and Sen et al. (2007) further supported enhanced the secretion levels of osteocalcin and osteonectin,
the role of α-tocotrienol in the modulation of phospholipase A2 increased alkaline phosphatase activity, and upregulated collagen
activities and 12-lipoxygenase, which are involved in glutamate- type I mRNA and Runx2 protein expressions in osteoblastic
induced neuronal cell death. MC3T3-E1 cells (Xu et al., 2018). Several studies have also
An emerging role for tocopherols and tocotrienols in reached a similar finding, in which tocopherol and tocotrienol
response to neuroinflammation has been demonstrated and have an antiosteoporotic activity. An animal study has shown
the occurrence of its positive effects on oxidative damage that a diet supplemented with γ-tocopherol increased bone mass
and Alzheimer pathology has been proposed. The proposed in male rats (Shuid et al., 2010). Muhammad et al. (2012)
aspects in the neuroinflammatory activity of this vitamin and Mohamad et al. (2012) further revealed that feeding with
including the regulation of Alzheimer-associated enzymes such a diet containing α-tocopherol promotes fracture healing and
as COX-2, 5-lipoxygenase (5-LOX), and nicotinamide adenine preserves bone mass in the estrogen-deficient rat. Findings from
dinucleotide phosphate (NADPH) oxidase (Block, 2008; Chu a population-based study mirror some of those from preclinical
and Praticò, 2011). Further, research evidence indicates that data obtained from an in vivo study. Data from a cross-sectional
tocopherols and tocotrienols are of benefit in the stimulation study showed a positive relationship between bone mineral
of phosphoprotein phosphatase 2A (PP2A), a phosphatase that density and α-tocopherol level in elderly Chinese population (Shi
plays a crucial role in tau homeostasis which is lowered in human et al., 2016).
Alzheimer’s disease brains (Voronkov et al., 2011). Moreover, In addition to the effects observed on neuroinflammation and
data from clinical evidence have shown that tocopherols and osteoporosis, a beneficial effect of tocopherols and tocotrienols
tocotrienols supplementation in Alzheimer’s patients reduces supplementation has also been documented on the incidence
lipid peroxidation by up to 60% compared with that of the of cardiovascular disease. The formation of macrophage foam
control (Morris et al., 2005). In this regard, post-mortem cells is a characteristic and an early onset of atherosclerosis
analysis of cerebrospinal fluid found that α-tocopherol levels (Yang et al., 2017). The aortas of cholesterol-administered
were positively associated with perceptual speed and Alzheimer’s rabbits have typical atherosclerotic lesions and show increased
disease pathology in patients (Hensley et al., 2011). Overall, both in CD36 mRNA expression. Administration of tocopherols

and tocotrienols decreased cholesterol-induced atherosclerotic to the swelling of the lower legs and feet, lung, liver, and the
lesions and downregulated CD36 mRNA expression. The lining of the intestine (Motohashi et al., 2017). Heart failure is
decrease of CD36 scavenger receptor expression, indicating characterized by a loss of contractile function caused by energy
the role of tocopherols and tocotrienols in the reduction of depletion in mitochondria linked to a low level of UQ. It was
foam cell formation and atherosclerosis (Ozer et al., 2006). evident that UQ oral supplementation alleviated the endothelial
These data are in line with the previous study reported in dysfunction and the cardiac contractility (Peres et al., 2017).
vitro for macrophages and human smooth muscle cells, in Congestive heart failure is associated with a low level of UQ
which α-tocopherol inhibits uptake of oxLDL by downregulating in tissues and blood. An animal study showed that UQ reduces
CD36 expression (Devaraj et al., 2001). Previous studies have the lipid hydroperoxides concentration in atherosclerotic lesions
also reported that feeding Apoe (–/–) mice with tocopherols and the atherosclerotic lesions in the aorta (Littarru and Tiano,
and tocotrienols downregulated the expression of CD36 and 2007). Frei et al. (1990) exploring the impact of UQH2 on
upregulated the transcriptional activity of LXRα, ABCA1, and oxidative stress using liposomes. The data showed that UQH2
peroxisome proliferator-activated receptor gamma (PPARγ ) protects membrane lipid peroxidation, with similar efficiency
(Tang et al., 2014). A similar dietary supplementation was also as α-tocopherol. oxLDL has been associated with coronary
found to decrease the phosphorylation of PPARγ and nuclear artery disease (Ivanova et al., 2017). Previous study found that
factor E2-related factor 2 (Nrf2) and induce upregulation of the lipid peroxidation rate of human low-density lipoprotein
their downstream targets including α-glutathione S-transferase (LDL) is inhibited concomitantly with UQH2 administration
(GSTα) and adenosine triphosphate-binding cassette transporter following exposure to peroxyl radicals (Stocker et al., 1991).
A1 (ABCA1) through inhibition of matrix metalloproteinase-1 These observations imply that UQ could be one of the most
(MMP-1) (Bozaykut et al., 2014). Indeed, data from a meta- active antioxidants in the modulation of LDL (Wang and Hekimi,
analysis included randomized-controlled trials from 1985 to 2016). Likewise, data from a population-based study reported
2015, including 287,304 participants demonstrated that a diet that patients with heart failure who consume UQ had a lower risk
containing tocopherols and tocotrienols is negatively linked to of mortality in addition to increasing exercise capacity (Lei and
cardiovascular mortality risk (Schwingshackl et al., 2017). Liu, 2017). UQ supplementation may also improve the quality of
Another age-related disease is arthritis, which causes pain life in patients with congestive heart failure (Oleck and Ventura,
during movement and subsequently promotes loss of function 2016).
in the affected limb (Espejo-Antúnez et al., 2013). Rossato In addition to the effects mentioned above, a beneficial
et al. (2015) reported that tocopherols and tocotrienols role of UQ supplementation has also been observed on
reduced pain reversed debilitating symptoms elicited by painful the incidence of type 2 diabetes. Data from randomized
inflammation. The reduction of cytokine production has also controlled clinical trials have demonstrated that supplementation
been demonstrated in animal models of inflammation and with UQ can significantly improve vascular dysfunction and
in humans with arthritis (Bhattacharya et al., 2012). Overall, decrease the glycemic response (Mantle, 2017). From the study
tocopherols and tocotrienols might be promising tools for the reviewed, it showed that UQ reduces oxidative stress and did
alleviation of oxidative stress and preventing age-related diseases. not lead to any adverse effects. Consistent with the study
The potential implications of tocopherols and tocotrienols on the reported by Mantle (2017), Hernández-Ojeda et al. (2012)
age-related diseases worth of further investigation in comparative also found that UQ enhances nerve conduction parameters of
randomized clinical trials. diabetic polyneuropathy and ameliorates oxidative stress without
significant undesirable effects. A study by Raygan et al. (2016)
Ubiquinone further supported that UQ increases insulin sensitivity and
Ubiquinone (UQ), also known as coenzyme Q10, is synthesized improves beta cell function in diabetic patients.
within the body cells or can also be obtained from the diet UQ plays a central role in the cellular dysfunction of
(Quinzii et al., 2007) (Figure 5). Fish and meat are the richest Parkinson’s disease patients (Zhu et al., 2017). UQ levels
sources of dietary UQ (Pravst et al., 2010). UQ also can be found were relatively low in the plasma, platelet-mitochondria, and
in liver, kidney, beef, heart, sardines, soy oil, and peanuts. UQ is blood of Parkinson’s disease patients (Sohmiya et al., 2004).
a naturally occurring vitamin-like molecule formed from redox- Treatment with UQ reduced the cellular pathophysiological
active benzoquinone head group conjugated to a poly-isoprenoid alterations linked to a mitochondrial dysfunction in Parkinson’s
side chain of species-specific length (6–10 subunits) (Wang and disease patients (Cooper et al., 2012). Shults et al. (2002)
Hekimi, 2016). UQ is a potent antioxidant to neutralize ROS further demonstrated that high concentration UQ administration
and protect the inner lining of the lymph, blood vessels, and may slow down the functional decline experienced by early-
endothelium (Motohashi et al., 2017). However, UQ levels reduce stage of Parkinson’s disease patients. Overall, lipid profiles,
with advancing age and subsequently develop to some of the systemic inflammation, and insulin sensitivity were improved
symptoms related to aging. The reduction of UQ levels during after administration of UQ and thus may provide a useful
aging could be one of the predominant factors to develop chronic approach for the alleviation of age-related diseases.
diseases (Motohashi et al., 2017). To protect mitochondrial oxidative damage, several
Compared to other tissue, heart muscle utilizes more energy mitochondrial-targeted antioxidants have been developed
and usually has the highest UQ level and a relatively sensitive and a great potential mitochondrial-targeted antioxidant is
to UQ deficiency. The weakening of the heart muscle may lead MitoQ. MitoQ is a derivative of ubiquinone which linked to TPP

FIGURE 5 | Molecular structures of ubiquinone and organosulfur compounds (S-allylcysteine, diallyl sulfide, diallyl disulfide, and diallyl trisulfide).
moiety by a 10-carbon alkyl chain (Murphy and Smith, 2007). anti-inflammation (Colín-González et al., 2015) in addition to
Much information indicates that the ubiquinol moiety of MitoQ alleviating several diseases (Kodai et al., 2015).
can react with superoxide and protect against peroxynitrite (Liu Several studies reported by Arreola et al. (2015) and Kim et al.
et al., 2018b). Animal studies have revealed that MitoQ protects (2001) evaluated S-allylcysteine in relation to proinflammatory
against oxidative damage such as hypertension (Pak et al., 2018) cytokine production and inflammatory markers. The data
and neurodegenerative disease (Yin et al., 2016). A study by showed that S-allylcysteine inhibits NO production and iNOS
Junior et al. (2018) further supported that MitoQ improves expression in vitro study. Data reported by Liu K. L. et al.
mitochondrial dysfunction in heart dysfunction induced by (2006) have shown that diallyl disulfide inhibits the production
pressure overload, by reducing hydrogen peroxide formation of NO and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-
in rats. Emerging research evidence indicates that MitoQ may stimulated BV2 microglia in a dose-dependent manner. In a
possess beneficial effects on tubular injury (Dare et al., 2015). further study focused on inflammation outcomes, Liu K. L.
Notably, data from an animal study have stated that MitoQ et al. (2006) compared different groups of RAW 264.7 cell line
inhibited amyloid-β peptide (Aβ) induced oxidative stress, a murine macrophages that treated with diallyl trisulfide, diallyl
critical component of Alzheimer’s disease, and reversed early disulfide, and diallyl sulfide, respectively. The data demonstrated
cognitive decline (Zhang et al., 2018). Despite the beneficial that diallyl sulfide showed the most suppressive effect on NO
effects of MitoQ on neurodegenerative disease was reported production and iNOS expression, suggesting that it was linked
in vivo, not all studies demonstrated such a link. Data from the to the number of sulfur atoms of the organosulfur compounds.
double-blind clinical trial of Parkinson disease patients failed to Organosulfur compounds not only modulate glutathione and
show any benefit in delaying the pathologic process of Parkinson phase II enzymes and inhibit inflammatory mediators, they also
disease during 12 months administration of MitoQ (Snow et al., inhibit several cancers. Previous findings suggest that a diet
2010). Overall, these findings demonstrated that MitoQ might supplemented with diallyl trisulfide, diallyl disulfide, and diallyl
be promising tools for pathological changes of mitochondrial sulfide suppressed cancers induced by chemical carcinogens
oxidative damage associated with age-related diseases. (Huang J. et al., 2015; Su et al., 2016; Kiesel and Stan, 2017).
In support of this, an animal study has demonstrated that oral
Organosulfur Compounds administration of diallyl trisulfide at a dosage of 1–2 mg per day
Organosulfur compounds mainly present in vegetable species for 13 weeks significantly suppressed the progression of invasive
belonging to Allium genus and Brassicaceae family. Functional carcinoma and multiplicity of pulmonary metastasis (Singh et al.,
organosulfur compounds in Allium have been used in folk and 2008). Several studies have also reached a similar finding, in
traditional medicine in the last centuries (Petropoulos et al., which diallyl trisulfide and diallyl sulfide have an antiproliferative
2017). Sulfur compounds from Allium play a critical role in activity against bladder, pancreatic, and skin cancers (Ma H. -
defense (Nwachukwu et al., 2012). Sulfur is the compound of Fe- B. et al., 2014; Shin et al., 2014; Shan et al., 2016). Collectively,
S clusters and several amino acids for enzymes activity (Gruhlke regular consumption of food rich in organosulfur compounds
and Slusarenko, 2012). Fe-S clusters are vitally important for the may become a safe and successful strategy to alleviate oxidative
origin of life, particularly acetyl-CoA, RNA, and DNA (Fuss et al., stress and improve age-related chronic disease conditions.
2015). Organosulfur compounds (Figure 5) usually present in Despite antioxidants pharmacological properties were
onion, garlic, and Chinese chive, which may benefit a certain reported in vitro and in vivo, some of the clinical expectations of
group of the population because they appear to combat oxidative antioxidant-based therapies have been frequently disappointed.
stress associated age-related diseases such as cardiovascular Low stability and the poor aqueous solubility limit the
disease (Lu et al., 2015; Seki and Hosono, 2015; Wang et al., therapeutic potential of antioxidants. This complication
2015), diabetes (Akash et al., 2014; Sambu et al., 2015), obesity has hampered the quantity of antioxidant absorbed, which
(Lai et al., 2014), and neuroinflammation (Colín-González severely limit its bioavailability. Nanotechnology has emerged
et al., 2015; Wen and Zhu, 2015). Organosulfur compounds as a promising drug delivery system (Dehghanizade et al.,
such as S-allylcysteine has anti-apoptotic, anti-oxidation, and 2018; García Calavia et al., 2018). Nanotechnology has received

a great attention as it can resolve problems linked to the additionally to identify the downstream mediators of oxidative
conventional therapeutic agents, such as lack of targeting pathways.
capability, poor water solubility, systemic toxicity, and Oxidative stress caused by an overproduction of ROS, mainly
nonspecific distribution (Sreelakshmi et al., 2018). Hence, due to an imbalance of oxidative to reducing species. It
the application of nanotechnology could enhance the efficacy has been suggested that excessive ROS production may lead
and improve their bioavailability by increasing solubility, to an upregulation of oncogene gene and the formation of
enhancing plasma half-life, preventing degradation in the mutagen compounds, which trigger proatherogenic activity and
intestinal environment, and elevating permeation in the small inflammation. Yet, longevity is not merely embedded in the
intestine (Hu et al., 2017). genes; in fact, food rich in antioxidants may play an essential
role in the immune system, production of cellular energy, as well
CONCLUSIONS AND FUTURE as scavenge the ROS. The broad spectrum of processes in which
the antioxidant molecules are involved suggests that a protective
PERSPECTIVE
role of antioxidants in the pathogenesis of age-related diseases.
Despite a large part of literature exploring on the accumulation Thus, an antioxidant can be a useful approach for healthspan
and the origin of ROS, current antioxidant-based therapies lack extension as well as lifespan extension. Despite antioxidant may
of specificity for dysfunctional tissues, cells, and organelles, and not serve as drugs, they hold great promising and indirectly
thus may not reach an effective concentration at the target site provide leads in future use to combat age-related diseases. The
of pathologic oxidative stress. Additionally, antioxidants target potential implication of antioxidant in relation to age-related
huge amounts of reactive oxygen intermediates and are unable diseases to replace conventional therapies could be significant
to modulate specific intermediate in the oxidative reaction, and and is warranted to be elucidated in long-term clinical trials.
subsequently leading several therapeutic strategies are unfocused.
Mitochondria-targeted antioxidants hold great promising and AUTHOR CONTRIBUTIONS
may serve as a useful approach for the alleviation of age-
related diseases. However, further investigations are warranted to BT and W-P-PL conceived and designed the review and wrote
improve the potency of antioxidant-based therapies. Moreover, the manuscript. MN edited the manuscript. HS wrote the
it is worth to underline the need of exploring the role of iron- manuscript. All authors read and approved the final manuscript.
mediated oxidative damage through Fenton reaction to further
ascertain the contribution of mitochondrial dysfunction and iron ACKNOWLEDGMENTS
accumulation to the progression and pathologic development of
age-related diseases. Data available on the interaction between We would like to thank the Ministry of Science, Technology,
chelating agents and antioxidants are limited, and further and Innovation (MOSTI), Malaysia (project no. 02-01-04-
investigation may lead to the development of potent therapeutic SF2141) for financial support and Putra Grant (UPM/700-
agents and novel biomarkers targeting specific disease tissues, 2/1/GPB/2017/9549900).
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published: 16 October 2018

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Antioxidants Age-related diseases Findings References

Glutathione Atherosclerosis No effect Mills et al., 2000

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Antioxidants Age-related diseases Findings References

Tocopherols and Cancer No effect Lonn et al., 2005

Carotenoids Most carotenoids are tetraterpenoids, derive from 8 isoprene

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