Oxidative Stress, Aging, and Diseases (Liguori 2018)

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Oxidative stress, aging, and diseases

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Clinical Interventions in Aging
Ilaria Liguori 1 Abstract: Reactive oxygen and nitrogen species (RONS) are produced by several endogenous
Gennaro Russo 1 and exogenous processes, and their negative effects are neutralized by antioxidant defenses.
Francesco Curcio 1 Oxidative stress occurs from the imbalance between RONS production and these antioxidant
Giulia Bulli 1 defenses. Aging is a process characterized by the progressive loss of tissue and organ function.
Luisa Aran 1 The oxidative stress theory of aging is based on the hypothesis that age-associated functional
losses are due to the accumulation of RONS-induced damages. At the same time, oxidative
David Della-Morte 2,3
stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic
Gaetano Gargiulo 4
obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and
Gianluca Testa 1,5
cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have
Francesco Cacciatore 1,6 been identified and may provide important information about the efficacy of the treatment,
Domenico Bonaduce 1 guiding the selection of the most effective drugs/dose regimens for patients and, if particu-
Pasquale Abete 1 larly relevant from a pathophysiological point of view, acting on a specific therapeutic target.
1
Department of Translational Given the important role of oxidative stress in the pathogenesis of many clinical conditions
Medical Sciences, University of and aging, antioxidant therapy could positively affect the natural history of several diseases,
Naples “Federico II”, Naples, Italy;
2
Department of Systems Medicine, but further investigation is needed to evaluate the real efficacy of these therapeutic interven-
University of Rome Tor Vergata, tions. The purpose of this paper is to provide a review of literature on this complex topic of
Rome, Italy; 3San Raffaele Roma Open
ever increasing interest.
University, Rome, Italy; 4Division of
Internal Medicine, AOU San Giovanni Keywords: elderly, reactive oxygen species, reactive nitrogen species, antioxidants
di Dio e Ruggi di Aragona, Salerno,
Italy; 5Department of Medicine
and Health Sciences, University of Pathophysiology of oxidative stress
Molise, Campobasso, Italy; 6Azienda
Ospedaliera dei Colli, Monaldi
Free radicals are highly reactive atoms or molecules with one or more unpaired
Hospital, Heart Transplantation Unit, electron(s) in their external shell and can be formed when oxygen interacts with
Naples, Italy
certain molecules.1 These radicals can be produced in cells by losing or accepting
a single electron, therefore, behaving as oxidants or reductants.2 The terms reactive
oxygen species (ROS) and reactive nitrogen species (RNS) refer to reactive radical
and non-radical derivatives of oxygen and nitrogen, respectively.3 Reactive oxygen
and nitrogen species (RONS) are produced by all aerobic cells and play an important
role in aging as well as in age-related diseases.4 RONS generation is not only limited to
determine deleterious effects but also involved in the extraction of energy from organic
molecules, in immune defense, and in the signaling process.5 There are endogenous
and exogenous sources of RONS:
• Endogenous sources of RONS include nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase, myeloperoxidase (MPO), lipoxygenase, and angio-
Correspondence: Pasquale Abete tensin II.6 NADPH oxidase is the prevalent source of the radical superoxide anion
Department of Translational (O2•) which is formed by the one-electron reduction of molecular oxygen, with
Medical Sciences, University of
Naples “Federico II”, Via S Pansini, electrons supplied by NADPH, during cellular respiration. Most of the O2• is
Naples 80131, Italy dismutated into the hydrogen peroxide (H2O2) by superoxide dismutase (SOD).5
Tel +39 081 746 2270
Fax +39 081 746 2339
H2O2 is not a free radical because it has no unpaired electrons, but it is able to form
Email [email protected] the highly reactive ROS hydroxyl ion (OH•) through the Fenton or Haber–Weiss
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Liguori et al Dovepress
reaction. Hydroxyl radicals are extremely reactive and lesions including 2-hydroxy adenine, 8-oxoadenine,
react especially with phospholipids in cell membranes 5-hydroxycytosine, cytosine glycol, thymine, and glycol. The
and proteins. In neutrophils, H2O2 in the presence of most mutagenic consequences of oxidative stress on DNA
chloride and MPO can be converted to hypochlorous are 8-oxo-7,8-dihydro-guanine (8-oxoGuo) and 8-oxo-7,8-
acid, an ROS particularly damaging cellular proteins.5 dihydro-2′deoxyguanosine (8-oxodG) lesions, but, among
Nitric oxide (NO) is produced from l-arginine by three these, the most recurring is 8-oxoGuo, which can result in
main isoforms of nitric oxide synthase (NOS): epithe- G-to-T transversion events.13
lial NOS, related to vasodilation and vascular regula- Antioxidant defense protects biological systems from
tion, neuronal NOS, linked to intracellular signaling, free radical toxicity and includes both endogenous and
and inducible NOS, activated in response to various exogenous molecules.
endotoxin or cytokine signals.7 Finally, O2 may react • Endogenous antioxidants include enzymatic and non-
with NO to form another relatively reactive molecule, enzymatic pathways.
peroxynitrite (ONOO−).5,6 The primary antioxidant enzymes are SOD, catalase
• Exogenous sources of RONS are air and water pol- (CAT), and glutathione peroxidase (GSH-Px). As men-
lution, tobacco, alcohol, heavy or transition metals, tioned above, O2 is converted by SOD to H2O2, which is
drugs (eg, cyclosporine, tacrolimus, gentamycin, and decomposed to water and oxygen by CAT, preventing
bleomycin), industrial solvents, cooking (eg, smoked hydroxyl radicals production. Additionally, GSH-Px
meat, waste oil, and fat), and radiation, which inside the converts peroxides and hydroxyl radicals into nontoxic
body are metabolized into free radicals.8 forms by the oxidation of reduced glutathione (GSH)
RONS, whether they are endogenous or exogenous, into glutathione disulfide and then reduced to GSH
cause oxidative modification of each of the major cellular by glutathione reductase. Other antioxidant enzymes
macromolecules (carbohydrates, lipids, proteins, and DNA),6 are glutathione-S-transferase and glucose-6-phosphate
which can also be used as markers of oxidative stress.9 dehydrogenase.14
Several oxidative changes in proteins have been described. The non-enzymatic antioxidants are molecules that inter-
Protein carbonyl (PC) is formed by Fenton reaction of oxi- act with RONS and terminate the free radical chain reac-
dants with lysine, arginine, proline, and threonine residues tions: bilirubin, α-tocopherol (vitamin E), and β-carotene
of the protein side chains.10 Carbonyl groups may also derive are present in blood while albumin and uric acid account
from the binding of aldehydic lipid oxidation products to for 85% of antioxidant capacity in plasma.15
lysine, cysteine, or histidine residues called Michael-addition • Exogenous antioxidants include ascorbic acid (vitamin C),
reactions.9 Reactions between RNS and tyrosine residues which scavenges hydroxyl and superoxide radical anion,
free or within polypeptide sequences induce the formation α-tocopherol (vitamin E), which is involved against
of nitrotyrosine (NT).9 Low-density lipoproteins (LDLs) lipid peroxidation of cell membranes, and phenolic anti-
are the major carriers of cholesterol to body tissues. The oxidants, which include stilbene derivatives (resveratrol,
oxidation of LDL is a complex process during which both phenolic acids, and flavonoids), oil lecitinas, selenium,
the protein and the lipids undergo oxidative changes that zinc, and drugs such as acetylcysteine.16 Oxidative stress
can cause cholesterol accumulation.11 Poly-unsaturated fatty occurs when there is an imbalance between the formation
acids (PUFAs), in particular linoleic and arachidonic acids, and the removal of RONS because of an overproduction
are other important targets of lipid peroxidation, mediated and/or an impaired ability to neutralize them or to repair
by hydroxyl and peroxyl radicals. Depending on the type the resulting damage.6
of PUFAs undergoing lipid oxidation, several different
reactive aldehydes are produced, such as trans-4-hydroxy- Oxidative stress and theory of aging
2-nonenal (4-HNE), malondialdehyde (MDA), and isopros- Aging is the progressive loss of tissue and organ function
tanes (F2-IsoPs).9 The amino groups of lysine and arginine over time.17 The free radical theory of aging, later termed as
react with the carbonyl groups of carbohydrates in a process oxidative stress theory of aging, is based on the structural
called glycoxidation, resulting in advanced glycation end damage-based hypothesis that age-associated functional
products (AGEs). Major AGEs include hydroimidazolone, losses are due to the accumulation of oxidative damage to
N∈-carboxymethyl-lysine, pentosidine, and glucosepane.12 macromolecules (lipids, DNA, and proteins) by RONS.18
Oxidative damage to DNA results in several mutagenic The exact mechanism of oxidative stress-induced aging is
758 submit your manuscript | www.dovepress.com Clinical Interventions in Aging 2018:13

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still not clear, but probably increased RONS levels lead to conditions, including Alzheimer’s disease (AD), brain tissue
cellular senescence, a physiological mechanism that stops biopsies show increased levels of p16, MMP, and IL-6.21
cellular proliferation in response to damages that occur Chronic obstructive pulmonary disease, biliary cirrhosis,
during replication. Senescent cells acquire an irrevers- cholangitis, and osteoarthritis share several damaging SASP
ible senescence-associated secretory phenotype (SASP) profiles including IL-6, IL-8, and MMP.1 The induction of
involving secretion of soluble factors (interleukins, epithelial to mesenchymal transition mediated by RONS
chemokines, and growth factors), degradative enzymes promotes cancer metastasis.22 In synthesis, given the close
like matrix metalloproteases (MMPs), and insoluble pro- relationship between oxidative stress, inflammation, and
teins/extracellular matrix (ECM) components.1,19 RONS aging, the oxidation-inflammatory theory of aging or oxi-
induce cellular senescence acting on various components inflamm-aging has been proposed: aging is a loss of homeo-
of SASP: stasis due to a chronic oxidative stress that affects especially
• regulation of mammalian target of rapamycin complexes’ the regulatory systems, such as nervous, endocrine, and
functions;1 immune systems. The consequent activation of the immune
• production of IL-1α leading to a proinflammatory state, system induces an inflammatory state that creates a vicious
which increases nuclear factor kappa-B (NFκB) activity circle in which chronic oxidative stress and inflammation
and epithelial–mesenchymal transition and tumor meta- feed each other, and consequently, increases the age-related
static progression;1 morbidity and mortality.23
• induction of MMPs expression, which is associated The connection between oxidative stress and the main
with age-related and chronic diseases such as cancer, age-related diseases is described in the following sections
Alzheimer’s, atherosclerosis, osteoarthritis, and lung (Figure 1).
emphysema;1
• inhibition of FOXO (Forkhead box) proteins activity, Oxidative stress and CVDs
which is involved in insulin/insulin-like growth factor- CVDs are a leading cause of morbidity and mortality in
1-mediated protection from oxidative stress;1 the elderly, and atherosclerosis plays a crucial role as main
• reduction of sarco/endoplasmic reticulum Ca2+-ATPase causal event.24 Several studies have proven that heart toler-
activity leading to cardiac senescence; ance to oxidative stress decreases with age because of a
• inhibition of sirtuins activity leading to an increased reduction in the concentrations of the antioxidant enzymes
production of RONS by SOD inhibition, a proinflam- (ie, GSH-Px and SOD), contributing to the development of
matory state by preventing their inhibition of tumor CV alterations.25
necrosis factor alpha (TNFα) and NFκB, and tumorigenic The evidence currently available links atherosclerosis
effect by preventing their inhibitory effect on c-Jun and with oxidized LDL-cholesterol (oxLDL) as the compound
c-Myc;20 mainly responsible for its production, also in elderly.26
• regulation of p16INK4a/pRB and p53/p21 pathways In fact, different studies showed a significant association
leading to senescence.1 between oxLDL and higher arterial stiffness, independent
of other traditional CVD risk factors.27 A study conducted in
Oxidative stress and age-related 2,944 healthy women (aged 30–79 years) underlined increases
diseases in oxLDL levels in plasma after 50 years.28 The increase of
Oxidative stress, cellular senescence, and consequently, oxLDL with aging may amplify LDL atherogenicity because
SASP factors are involved in several acute and chronic patho- of the prooxidant and proinflammatory environments that
logical processes, such as CVDs, acute and chronic kidney characterize elderly subjects.26 Conversely, data for the
disease (CKD), neurodegenerative diseases (NDs), macular InCHIANTI dataset, a 9-year follow-up population-based
degeneration (MD), biliary diseases, and cancer. Cardiovas- study, showed no association between higher oxLDLs levels
cular (CV) risk factors (ie, obesity, diabetes, hypertension, (measured with antibody 4E6) and CVD/cardiac mortality,
and atherosclerosis) are associated with the inflammatory suggesting that in advanced age, the prognostic information
pathway mediated by IL-1α, IL-6, IL-8, and increased added by oxLDLs might not be significant.29 Moreover,
cellular senescence.1 Moreover, vascular calcification is the development of oxidative stress contributes to vascular
linked to an SASP-driven osteoblastic transdifferentiation of endothelial dysfunction with aging. In healthy adults varying
senescent smooth muscle cells. In many neurodegenerative in age, brachial artery flow-mediated dilation is inversely
Clinical Interventions in Aging 2018:13 submit your manuscript | www.dovepress.com

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Abbreviations: 4-HNE, trans-4-hydroxy-2-nonenal; 8oxodG, 7,8-dihydro-8-oxo-2′-deoxyguanosine; 8oxoGuo, 7,8-dihydro-8-oxoguanosine; ADMA, asymmetric dimethyl
l-arginine; AGEs, advanced glycation end products; CKD, chronic kidney disease; CVDs, cardiovascular diseases; F2-IsoPs, F2-isoprostanes; MDA, malondialdehyde; MPO,
myeloperoxidase; NDs, neurodegenerative diseases; NT, nitrotyrosine; oxLDL, oxidized low-density lipoprotein; PC, protein carbonyl; Prx, peroxiredoxins; P-VASP,
phosphorylated vasodilator-stimulated phosphoprotein; Trx, thioredoxin.
related to NT in vascular endothelial cells.30 Furthermore, activation of four important molecular pathways involved
the expression of endhotelin-1, the most effective vasocon- in hyperglycemia-induced oxidative tissue: activation of
strictor molecule produced by the vascular endothelium, is protein kinase C (PKC), increased hexosamine pathway
increased in vascular endothelial cells of older compared flux, increased AGEs, and increased polyol pathway flux.36
with younger adults and inversely related to endothelium- In particular, the activation of the AGEs pathway can damage
dependent dilation and positively related to NT.31 Endothelial cells modifying the regulation of gene transcription, the
dysfunction and vascular remodeling are recognized as signaling between the matrix and other cells and blood
early determinants in the development of hypertension and proteins (eg, albumin), causing them to bind to AGEs
atherosclerosis.32 receptors (RAGEs) on macrophages/mesangial cells and
increase the production of growth factors and proinflam-
Oxidative stress and diabetes matory cytokines.37 Regarding the geriatric population, a
Diabetes mellitus (type 1 and 2) is a metabolic disease associ- study conducted on 61 elderly subjects has shown increased
ated with increased formation of free radicals and decreased levels of antioxidants (ie, CAT and GSH-Px) in subjects with
antioxidant potential, leading to macro- and microvascular impaired glucose tolerance (IGT), compared with healthy
complications.33 The precise mechanism by which oxidative controls, and increased levels of oxidative stress biomarkers
stress may accelerate the development of complications (ie, MDA) in T2D, but not in IGT group. These results sug-
in diabetes is only partly known. Oxidant stress in type 2 gest that there is an increased oxidative stress in the elderly
diabetes (T2D) promotes prothrombotic reactions, leading T2D patients, which can be partly balanced by increased
to CV complications.34 Diabetes damages can be considered antioxidant defense system in subjects with IGT.38
tissue-oxidative-damaging effects of chronic hyperglycemia.
Increased intracellular glucose leads to an increased RONS Oxidative stress and COPD
production, which exceeds the antioxidant capability of the COPD is a major cause of morbidity and mortality
cell to neutralize them.35 RONS induce, in this way, the worldwide39 and its prevalence increases with age.40 Several

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mechanisms related to aging are potentially involved in its dilatation that contributes to hypertension. NO levels are
pathogenesis, such as shortened telomere length, cellular also reduced because of the lack of its precursor l-arginine,
and immune senescence, inflammation and also oxidative which is formed from l-citrulline in the kidney. Superoxide
stress.41 RONS in COPD result from both cellular and envi- anion is also capable of reacting with NO itself forming per-
ronmental sources. Environmental oxidants from cigarette oxynitrite, which can oxidize NOS making it unstable. This
smoke activate macrophage and epithelial cells triggering unstable NOS will further augment superoxide production.46
proinflammatory cytokine and chemokine generation, NOS activity is also inhibited by NOS inhibitors, such as
which induce immune response. Released proteases break the asymmetric dimethyl-arginine (ADMA), which accu-
down connective tissues in the lung, potentially resulting mulates in CKD and contributes to hypertension through
in chronic bronchitis or emphysema. Moreover, excessive vasoconstriction.47 CKD patients also have high levels of
RONS released via oxidative bursts of polymorphonuclear homocysteine, which raises ROS production, and ADMA,
leukocytes (PMNs) and alveolar macrophages have been reduces NO synthesis, and increases the risk of CV events.45
shown to inhibit antiprotease processes and accelerate the Endothelial dysfunction, induced by oxidative stress, changes
degradation of lung tissue. RONS also delay the resolution vascular permeability and leads to the entry of LDL choles-
of inflammation via compromising the phagocytic ability of terol into intimal layer and increased oxLDL levels, which
alveolar macrophages, leading to necrosis and emphysema. are involved in the atherosclerosis process, as mentioned
Likewise, long-term cigarette smoke exposure impairs earlier.48 ADMA-induced endothelial dysfunction leads to
PMNs and alveolar macrophage phagocytosis and antigen- proteinuria, a sign of glomerular damage associated, in turn,
presentation functions, which could predispose patients with proinflammatory cytokines secretion, which increases
to bacterial/viral infection.42 Several studies have shown the production of ROS, worsening renal damage.45 Finally,
increased levels of biomarkers of oxidative stress in COPD in a state of oxidative stress, the oxidation of red blood cells
patients, such as 8oxodG, NT, F2-IsoPs, AGEs, and PC, with lipid membranes decreases their elasticity shortening their
a strong correlation with the severity of airflow limitation lifespan and increasing the hemolysis probability. This might
in COPD elderly patients.41 In particular, some authors have explain the cause of anemia in patients with CKD in addition
shown that several age-related diseases, including COPD, to the reduction of erythropoietin synthesis.49 In particular, the
are associated with a skeletal muscle dysfunction. Oxidative global prevalence of CKD is rising, particularly among the
stress is a major player in the etiology of this condition in the elderly population, and CKD accelerates normal aging and
elderly, and specifically, protein carbonylation was shown to leads to worsening frailty in elderly patients through several
modify the function of key enzymes and structural proteins mechanisms, in particular, oxidative stress.50
involved in muscle contractile performance.10 Furthermore, a
decline in some isoforms of the receptor for AGEs has been Oxidative stress, cognitive impairment,
detected in COPD elderly patients, and a study has shown and dementia
that its levels have a significant and independent association Cognitive impairment and dementia affect life quality and
with FEV1, FEV1/FVC, and diffusing capacity of the lung for life span in the elderly. Not only NDs, which include AD,
carbon monoxide in COPD patients, suggesting that it may Parkinson’s disease (PD), Huntington’s disease (HD),
be a marker of disease severity and consequently a marker and amyotrophic lateral sclerosis (ALS), but also vascular
of accelerated aging in this cohort.41,43 dementia have a massive impact especially in aging
populations – progressive loss of memory, impairments in
Oxidative stress and CKD the movement, or progressive inability to move.51,52 Oxi-
Oxidative stress plays a pivotal role in the progression of dative stress has been shown to play a pivotal role in the
CKD, through glomerular damage and renal ischemia and, pathophysiology of dementia.53 In fact, several studies have
indirectly, with inflammation, hypertension, and endothelial evaluated the relationship between the levels of some oxi-
dysfunction.44 CKD patients are in a chronic inflammation dative stress biomarkers and cognitive function, evaluated
state characterized by the activation of PMNs and monocytes. with Mini-Mental State Examination (MMSE). A recent
These inflammatory cells increase the secretion of NADPH study showed that increased oxidative stress biomarkers
oxidase and MPO that enhance the formation of ROS.45 (ie, MDA, GSH-Px, and PC) correlated with raised levels of
Leukocytes of CKD patients produce superoxide anions, inflammatory cytokines and both were associated with low
which inactivate NO, reducing the ability of blood vessels cognitive performance in institutionalized elderly people.54

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Another study showed that, despite age being the principle cells or recruit other inflammatory cells leading to additional
cause of cognitive decline, cognitive impairment is slower RONS production that amplifies the damage.63 In particular,
in patients with high GSH-Px activity, but high GSH levels RONS and inflammatory cytokines, such as TNFα, activate
seem to accelerate cognitive decline in the elderly. This the transcription factor NFκB, which induces the expression
seems to be a paradoxical finding because high intracellular of genes involved in cell proliferation, apoptosis, and carcino-
GSH should have a protective function against cell damage genesis.64 Chronic inflammation is also associated with angio-
caused by free radicals. A possible hypothesis is that, as genesis, another characteristic of cancer, because RONS can
GSH is a substrate of GSH-Px, high GSH levels could be a also increase the expression of transcriptional factors (ie, c-fos
consequence of the increase in oxidative stress induced by and c-jun) involved in neoplastic transformation and enhance-
a reduction of GSH-Px activity.55 Other theories have been ment of cancer angiogenesis.63 Moreover, macrophages,
suggested to explain the involvement of oxidative stress in platelets, fibroblasts, and cancer cells are a major source
the pathophysiology of NDs. For example, oxidative stress of angiogenic factors (ie, fibroblast growth factor, vascular
is one of the conditions that induces stress granules (SGs) endothelial growth factor, and prostaglandins-E1 and E2),
formation. Nuclear SGs contain heat-shock transcription which increase the production of RONS and, subsequently,
factor 1/2 and pre-mRNA processing factors while cyto- increase the risk of cancer.62 The mutagenic/carcinogenic
plasmic SGs are composed of proteins and non-translating potential of RONS is due to their capability of reacting
mRNAs.53 Normal cytoplasmic SGs assemble in response to with DNA and chemically modifying it. In particular, ROS-
various stressful conditions and are degraded once the stress induced DNA damages can result in transcriptional arrest or
is absent. SGs can also form super-stable aggregates under induction/replication errors, or genomic instability, which
pathological conditions – more severe stress, mutations that are all associated with carcinogenesis.65 Among oxidized-
promote SG assembly or amyloid formation, or mutations DNA products, 8-oxodG and 8-nitroguanine are considered
that reduce their clearance.56 SGs produced in response to biomarkers for inflammation-induced carcinogenesis.62 There
acute stress are protective and antiapoptotic. In cognitive is a dramatic age-dependent escalation in cancer risk, and
impairment, the stress is a chronic condition that cannot be increased oxidative stress and oxidative stress and its damages
resolved; hence, SGs may interfere with neuronal function by over a lifetime may be responsible for this phenomenon.66
silencing transcripts and by sequestering important proteins In fact, there is an accumulation of RONS-induced DNA
such as ribonucleoproteins.53 Another hypothesis suggests damages with age, which is confirmed by the progressive and
the role of ROS and redox metals in the pathogenesis of statistically significant increase in the levels of 7,8-dihydro-
AD. Abnormal homeostasis of bioactive metals could be 8-oxo-2′-deoxyguanosine (8oxodG) observed with aging.62
involved in oxidative stress influencing AD – zinc directly On the basis of these considerations, chronic inflammation
affects amyloid-protein precursor,57 and aluminum, zinc, and oxidative stress should be considered high risk factors for
iron, and copper directly bind to amyloid promoting its cancer, especially in elderly people.66 Based on these analo-
aggregation.58–60 Similarly, the redox metals could promote gies, it should be recommended that elderly people should
Tau phosphorylation. ROS, amyloid, and Tau protein affect consume higher antioxidant compounds, but the efficacy of
the activity of N-methyl-d-aspartate (NMDA) receptors, antioxidant therapy in the prevention of carcinogenesis is
triggering an NMDA-mediated excessive influx of Ca2+ in currently under investigation.
post-synaptic neurons leading to a cascade of events that
increase ROS production, oxidative stress, Tau phosphoryla- Oxidative stress, sarcopenia, and
tion, and lipid peroxidation, ultimately leading to synaptic frailty
dysfunction responsible for AD.61 With improved life conditions and the availability of inno-
vative treatments, life expectancy and, consequently, the
Oxidative stress and cancer number of elderly in the population have increased.67 Aging
Many studies have demonstrated the direct relationship is associated with strength deficits that are related to frailty,
between chronic inflammation and carcinogenesis.62 The loss of independence, and physical disability.68 Reduction
main chemical effectors of these effects of the inflammatory in strength is due to both loss of muscle quantity, referred
response are free radical species derived from oxidative stress to as sarcopenia, and loss of muscle strength, termed as
induced by inflammation. RONS may directly or indirectly dynapenia.69 Skeletal muscles consume large quantities of
damage other chemical or structural components in target oxygen and can generate a great amount of RONS, whose

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accumulation is thought to be a common determinant in the $JLQJ

loss of both muscle quantity and quality, through several
mechanisms.70 First of all, with advancing age, the antioxi- 2[LGDWLYHVWUHVV ,QIODPPDWLRQ
dants defenses are compromised, and RONS accumulation
induces posttranscriptional modifications, which can be 6DUFRSHQLD
used as biomarkers of oxidative stress, such as the nitration

3UHFOLQLFDOIUDLOW\
and nitrosylation (ie, NT), carbonylation (ie, PC, 4-HNE), YXOQHUDELOLW\
and glycation (ie, AGEs).69 Second, RONS contribute to
sarcopenia also by increasing proteolysis and decreasing &OLQLFDOIUDLOW\
muscle protein synthesis, leading to a reduction in muscle &9'GHPHQWLDVWURNH
mass quantity.3 On the other hand, several mechanisms,

Figure 2 Relationship among oxi-inflamm-aging, preclinical and clinical frailty.
acting on the neuromuscular junction, are involved in Abbreviation: CVD, cardiovascular disease.
RONS-mediated reduction of muscle quality and strength.
First, RONS reduce acetylcholine release at the synaptic
performance.76 Since Fried’s phenotype of frailty focuses
cleft, which could lead to a failure in the generation of an
on physical frailty, the mechanisms proposed to explain the
action potential by the sarcolemma. Moreover, persistent
relationship between oxidative stress and frailty in the elderly
oxidative stress may change the morphology of the neuro-
are largely overlapped with those described above to explain
muscular junction causing a reduction in the innervation
how oxidative stress causes musculoskeletal system damag-
and fibers number. At the same time, RONS damage impair
es.74 In other words, frailty in these studies has been defined
excitation–contraction (EC) coupling, leading to a lower
with criteria of Fried’s frailty phenotype, ie, “primary” or
release of calcium from the sarcoplasmic reticulum. Finally,
“preclinical” frailty, which is not associated with a specific
RONS induce modification in actin and myosin structures
disease. In contrast, “secondary” or “clinical” frailty which
significantly reducing the cross-bridge cycling within the
is associated with known disability and/or comorbidity (ie,
myofibrillar apparatus.69 Sarcopenia is an important altera-
CVDs, NDs, CKD, T2D)77 could significantly increase the
tion occurring in the elderly and predicts frailty, poor quality
generation of RONS products.73
of life, and mortality.70 Thus, sarcopenia can be assessed
objectively and could be used as a predictor of these adverse
health outcomes and a therapeutic target for muscle-building Biomarkers of oxidative stress
interventions in the elderly.71 In particular, sarcopenia is The World Health Organization defined a biomarker as any
said to be the “biological substrate of physical frailty”,72 substance, structure, or process that can be measured in the
and the sarcopenia phenotype should be the central focus of body or its products and influence or predict the incidence
frailty assessment and intervention.71 A recent systematic of outcome or disease.78 A clinically useful biomarker
review on oxidative stress and frailty showed that preclinical should have specificity for a certain disease (diagnostic),
frailty is associated with higher peripheral levels of RONS have a prognostic value, and correlate with disease activity.9
biomarkers and lower antioxidant parameters. However, The most clinically relevant oxidative stress biomarkers
due to the cross-sectional design of the study, it was not are described in Table 110,12,26,27,30,31,38,41,43,54,62,66,79–101 and
possible to establish the directionality of the relationships Figure 1 and can be divided into RONS-induced modifica-
between RONS and frailty, since it could be bidirectional tions, markers of RONS generation, markers of antioxidant
(Figure 2).73 Moreover, the Framingham Offspring Study defense, and downstream functional markers of RONS-
showed increased levels of proinflammatory and oxidative induced damage.9
stress biomarkers (ie, C reactive protein and F2-IsoPs) both RONS-induced modifications biomarkers include
in pre-frail and frail elderly subjects.74 The same results • PC, whose increased levels are associated with low cogni-
were described in the elderly German population from the tive performance,54 CKD,79 COPD,10 and sarcopenia;80
ESTHER Cohort Study.75 All these studies defined frailty • AGEs, as mentioned above, derived from glycoxida-
according to Fried et al, who describe a physical frailty tion reactions. AGEs levels are increased in T2D12 and
phenotype consisting of the presence of three or more of the are an independent risk factor for both all-cause and
following characteristics: unintentional weight loss, weak- CV mortality,81 also among elderly patients with heart
ness, exhaustion, low physical activity, and slowness in motor failure.82 There is an age-dependent increase of serum

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Table 1 Overview of the most important oxidative stress biomarkers

Biomarkers Sample Disease References
RONS-induced modifications
PC Plasma High levels are associated with raised levels of cytokines and both are associated with 54
low cognitive performance in institutionalized elderly subjects.
Higher in CKD. 79
Associated with skeletal muscle dysfunction in elderly COPD patients. 10
Increased levels are associated with sarcopenia in elderly subjects. 80
AGEs Serum Higher in T2D. 12
Independent risk factor for both all-cause and cardiovascular disease mortality in 81, 82
elderly subjects with or without CHF.
Correlate with lipid profiles and atherosclerotic characteristics in the elderly. 83
Higher in elderly subjects with CKD. 81
Higher in elderly subjects with osteoporosis. 85
Decreased levels of their receptors are markers of severity and accelerated aging in 43
COPD elderly patients.
Skin Correlation with risk of exhaustion and low energy expenditure, but not with prevalent 87
or incident frailty in elderly subjects.
oxLDL Plasma High levels are associated with arterial stiffness and atherogenesis in the elderly. 26
Not predictive of cardiac mortality in elderly subject. 27
4-HNE Plasma Increased in elderly subjects with AD, PD, HD, and ALS pathologies. 88
F2-IsoPs Urine High levels are associated with depressed mood in community-dwelling elderly subjects. 90
High levels in AMD. 91
High levels in AD and HD. 92
High levels in CKD and correlate with disease progression. 79
High levels in COPD elderly patients. 41
MDA Plasma Increased levels correlate with raised levels of inflammatory cytokines and both are 54
associated with low cognitive performance in institutionalized elderly subjects.
Increased in elderly subject with T2D but not with IGT. 38
Elevated in CKD, inversely related to GFR, and positively correlated with uremic toxins 79
and severity of glomerulosclerosis.
NT Plasma Nytrotyrosine levels are associated with vascular endothelial dysfunction with aging. 30, 31
Tissue Increased levels are associated with sarcopenia in elderly subjects. 93
8oxodG Urine Markers of inflammation-induced carcinogenesis increasing with aging. 62
High levels in CKD. 79
8oxoGuo Urine Markers of carcinogenesis in the elderly. 66
Markers of RONS generation
MPO Plasma MPO predicts endothelial dysfunction and the development of CHF in the elderly. 94
MPO predicts all-cause mortality in frail and very old community-dwelling people. 95
MPO levels are elevated in elderly with AD. 96
Markers of antioxidant defense
Trx Plasma Significantly increased in CHF compared with healthy elderly subjects. 97
Inverse relationship with GFR, suggesting a protective mechanism. 79
Prx Plasma Potential biomarker of AD in elderly subjects. 98
Potential useful risk stratification tool to predict mortality in elderly patients with 99
nonspecific complaints presenting to the emergency department.
Downstream functional markers of RONS-induced damage
ADMA Plasma Strong prognostic value for mortality and future CV events in the elderly. 100
Elevated in CKD and is an independent predictor of superoxide generation. 79
P-VASP Platelets Establish the efficacy of antiplatelet drugs in the adults and the elderly. 101
Abbreviations: 4-HNE, trans-4-hydroxy-2-nonenal; 8oxodG, 7,8-dihydro-8-oxo-2′-deoxyguanosine; 8oxoGuo, 7,8-dihydro-8-oxoguanosine; AD, Alzheimer’s disease;
ADMA, asymmetric dimethyl l-arginine; AGEs, advanced glycation end products; ALS, amyotrophic lateral sclerosis; AMD, age-related macular degeneration; CHF,
chronic heart failure; CKD, chronic kidney disease; CV, cardiovascular; F2-IsoPs, F2-isoprostanes; GFR, glomerular filtration rate; HD, Huntington’s disease; IGT, impaired
glucose tolerance; MDA, malondialdehyde; MPO, myeloperoxidase; NT, nitrotyrosine; oxLDL, oxidized low-density lipoprotein; PC, protein carbonyl; PD, Parkinson’s
disease; Prx, peroxiredoxins; P-VASP, phosphorylated vasodilator-stimulated phosphoprotein; RONS, reactive oxygen and nitrogen species; T2D, type 2 diabetes;
Trx, thioredoxin.

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AGEs levels, and in the elderly, AGEs levels positively
correlate with lipid profiles and atherosclerotic char-

2+G* QJP/
acteristics, suggesting that AGEs could be used as a
0RUWDOLW\
marker to predict atherosclerotic lesions.83 Increased
AGEs levels are also associated with chronic kidney

disease, predicting a greater decline of renal function.84
Accumulation of AGEs in the collagen matrix of bone
increases its stiffness and fragility; in fact, AGEs levels
are significantly higher in patients with osteoporosis.85
$UWKULWLV &23' 'LDEHWHV &.' &+)
Moreover, a recent interesting French study analyzed the
relationships between the accumulation of AGEs, assessed Figure 3 Chronic diseases, oxidative stress, and long-term mortality in community-
dwelling elderly subjects. Data from a previous study.102
by skin autofluorescence (AF), and frailty in 423 older Abbreviations: CHF, chronic heart failure; CKD, chronic kidney disease; 8-OHdG,
8-hydroxy-2′-deoxyguanosine.
community-dwellers aged $75 years, showing that the
accumulation of AGEs was not associated with prevalent
or incident frailty but with the 4-year risk of exhaustion (ie, COPD, CKD, chronic heart failure [CHF], and T2D)
and low energy expenditure.87 Nevertheless, increased in community-dwelling elderly subjects (Figure 3).102
levels of AGEs are associated with sarcopenia in elderly The most important marker of RONS generation is MPO.
subjects,86 while decreased levels of RAGEs are markers MPO is a leukocyte-derived enzyme released in inflamma-
of severity and accelerated aging in COPD patients;43 tory conditions, which catalyzes the formation of several
• oxLDL levels, as described in the section “Oxidative stress ROS and is involved in LDL oxidation and is considered
and CVDs”, correlate with arterial stiffness and athero- a major contributor in the formation and rupture of athero-
genesis in the elderly, not predicting mortality;26,27 sclerotic plaque.103 Moreover, MPO direct catalyzes the
• 4-HNE levels are elevated in elderly subjects with NDs consumption of NO resulting in endothelial dysfunction.94
(ie, AD, PD, HD, and ALS)88 and sarcopenia;89 Therefore, MPO levels independently predict endothelial
• F2-isoprostanes urinary levels are increased in several dysfunction and mortality for CVDs and CHF. Data from the
diseases frequently diagnosed in elderly patients, such as Aging and Longevity Study in the Sirente Geographic Area
depression,90 age-related macular degeneration (AMD),91 (ilSIRENTE Study), a prospective cohort study that collected
AD and HD,92 COPD,41 and CKD, where it correlates with data on all individuals aged $80 years living in a mountain
disease progression;79 community (n=363), showed that high plasma levels of
• MDA increased plasma levels correlate with low cogni- MPO are positively associated with all-cause death in frail
tive performance in institutionalized elderly subjects;54 its and very old persons living in the community, independent
levels increase in elderly subjects with T2D but not with of age, gender, and other clinical and functional variables.
IGT38 and in CKD, where its levels are inversely related to In particular, after adjusting for several clinical correlates of
glomerular filtration rate (GFR) and positively correlated mortality risk, baseline MPO plasma concentration emerged
with uremic toxins and severity of glomerulosclerosis;79 as an independent predictor of mortality.95 A study conducted
• NT levels are used as biomarkers of COPD41 and sarcope- on 3,733 elderly subjects measuring MPO levels showed an
nia93 in elderly subjects, and high levels are associated independent association between increased MPO levels and
with vascular endothelial dysfunction with aging;30,31 the development of CHF, particularly beyond myocardial
• DNA modifications, 8oxodG and 7,8-dihydro-8- infarction and traditional cardiac risk factors.94 Moreover,
oxoguanosine (8oxoGuo), are excreted into the urine and among age-related diseases, MPO levels are also elevated
measured with enzyme-linked immunosorbent assay. in elderly subjects with AD, showing that MPO might be an
Both are markers of inflammation and carcinogenesis in important molecular link between atherosclerosis and AD
the elderly.62,66 Furthermore, 8oxodG is also a marker of and probably a promising biomarker for the detection and
COPD41 and CKD in elderly subjects.79 In fact, data from risk stratification of AD patients.96
the “Osservatorio Geriatrico Campano” showed that high Markers of antioxidant defense include the following:
levels of oxidative stress, quantified with 8oxodH, are asso- • Thioredoxin, NADPH, and thioredoxin reductase (TrxR)
ciated with high mortality in age-related chronic diseases are important defense systems against oxidative stress,

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providing the electrons to thiol-dependent peroxidases and aging, several studies have been conducted to investigate
(peroxiredoxins) to remove RONS.104 Trx levels are the therapeutic effects of antioxidant therapy.
significantly increased in CHF compared with healthy
elderly subjects97 and its levels show an inverse relation- Vitamins
ship with GFR, suggesting a protective mechanism.79 The most extensively studied antioxidants are vitamin A, and
• Peroxiredoxins are thiol-specific proteins that react as its precursor β-carotene, vitamin C, and vitamin E.108 Several
scavenger of H2O2, peroxynitrite, and a wide range of large observational studies were conducted on the effect of
hydroperoxides.105 Peroxiredoxins are potential bio- intake of different vitamins and on the risk of CVDs, suggest-
markers of AD in elderly subjects98 and, interestingly, ing that higher intake of these vitamins significantly lowered
they could be a useful risk stratification tool to predict the risk of these pathologic conditions.109 Systematic reviews
mortality in elderly patients with nonspecific complaints and meta-analysis conducted by Cochrane group investiga-
presenting to the emergency department.99 tors to study the effect of vitamins on all-cause mortality
There are also two markers that reflect oxidative stress showed conflicting and, many times, disappointing results.
downstream of the RONS-induced damage: ADMA and In some trials, vitamins did not seem to significantly affect
phosphorylated vasodilator-stimulated phosphoprotein mortality, but in several other trials, they were administered
(P-VASP).9 alone or in combination showing a significant increase of
ADMA is a powerful inhibitor of NOS and also com- all-cause mortality.110 These conflicting findings can lead
petes with l-arginine for the binding site of this enzyme. to the conclusion that vitamins cannot be used as effective
Reduced production of endogenous NO coincides with high antioxidant therapeutic agents.
ADMA levels, engenders endothelial dysfunction, and this
dysfunction is reversed by l-arginine.106 In particular, in the Coenzyme Q10
randomly selected, community-based sample of 1155 elderly, Coenzyme Q10 (CoQ10), ubiquinone (oxidized form) or
aged 65–102 years, of the “Invecchiare in Chianti Study” ubiquinol (reduced form), is an endogenous lipid that takes
(InCHIANTI; aging in the Chianti area), higher ADMA part in the mitochondrial respiratory chain reactions. 111
levels independently predicted all-cause and CV mortality. Numerous pathological processes are associated with primary
Thus, ADMA could be used as a prognostic value for mortal- and secondary CoQ10 deficits, including mitochondrial
ity and future CV events.100 diseases, fibromyalgia, CVDs, NDs, cancer, T2D, male
P-VASP is probably the best-established marker for infertility, and periodontal disease.112 CoQ10 treatment is
physiological cyclic guanosine monophosphate (cGMP) safe in humans, and new formulations that increase CoQ10
signaling, because it is phosphorylated mainly by cGMP- absorption and tissue distribution have been developed. Oral
dependent protein kinases, and lowered P-VASP levels are administration of CoQ10 is a frequent antioxidant strategy in
indicative of pathological signaling.9 However, in human many of the abovementioned diseases providing a significant
blood samples, P-VASP levels are used to establish the effi- to mild symptomatic benefit.112
cacy of (or detect nonresponders to) antiplatelet drugs, also
in the elderly, as shown in the GENERATIONS trial.101,107 Selenium
Oxidative stress biomarkers may provide important Many of the physiological roles of the element selenium
information about the efficacy of a treatment, thus, providing (Se) are directly attributed to its presence within at least 25
guidance for the selection of the most effective drugs/dose proteins, named selenoproteins, collectively essential for
regimens for patients. In addition, if a biomarker of oxidative life and also involved in oxidative stress control.113 Several
stress is particularly relevant from a pathophysiological point selenoproteins have been characterized as antioxidant
of view, it may also be useful in research as a therapeutic enzymes, such as GSH-Px, TrxR, and iodothyronine deio-
target to identify novel treatments with antioxidant proper- dinases.114 Several clinical trials have provided convincing
ties. However, further investigations are needed to confirm evidence of the central role of this element in the preven-
and explore their potential clinical applications.9 tion and treatment of multiple diseases, such as CVDs,
atherosclerosis, diabetes mellitus, stroke, NDs, depression,
Therapeutic approach hypothyroidism, and cancer.115 However, there are some
Since it has been established that oxidative stress plays an controversies over whether Se administration increases
important role in the pathogenesis of many clinical conditions the risk of some neuronal diseases (ie, ALS) because of its

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neurotoxic effects – inhibition of prostaglandin D synthase in incidence of other pathologies, such as neurodegenerative
the brain, inhibition of squalene mono-oxygenase, increase conditions, cancer, and osteoporosis.118
in dopamine and its metabolites, inhibition of succinic
dehydrogenase, acetylcholine esterase and Na+/K+ ATPase, Other antioxidant agents
and induction of seizures.116 Additional experimental evi- Many studies have been conducted to identify new natural
dence is needed to determine the optimal level of Se daily antioxidants.2 In particular, even the fermented papaya prepa-
intake that can maximize health benefits, avoiding potential ration (FPP), produced by fermentation of Carica papaya
toxic effects.115 Linn by using yeast, is considered a food supplement that
exhibits antiinflammatory, antioxidant, and immunostimula-
Polyphenols tory functions that could be helpful against age-related and
Polyphenols are secondary metabolites of plants, and disease-related increase in oxidative stress. In fact, because of
they are found largely in fruits, vegetables, cereals, and the important role of oxidative stress in the pathophysiology
beverages. Typically, a glass of red wine contains about of chronic NDs, a study has been conducted to explore the
100 mg polyphenols.117 The phenolic compounds of wine effects of FPP in AD patients, by measuring urinary 8oxodG,
can be divided into flavonoids and nonflavonoids. Flavonoids showing that, after a supplementation with FPP 4.5 g/day
account for .85% of the phenolic components in red wine for 6 months, urinary levels of 8oxodG were significantly
and include different molecules, especially quercetin, and decreased (14.1±1.7 ng/mL to 8.45±1.1 ng/mL, p,0.01),
nonflavonoids include mainly resveratrol.118 Quercetin is with no significant changes in controls, showing a potential
an antioxidant agent present in wine that has been shown to beneficial effect of FPP in patients with neurodegenerative
prevent or delay the initiation of CVDs or cancer through conditions, such as AD.124 Given the reported inverse rela-
different biological effects. Its mechanisms of action are not tionship between the dietary intake of antioxidant-rich food
completely understood, but it has shown an antiinflammatory and the incidence of human diseases, there has been a global
effect through a decrease of TNFα and IL-1β and suppression trend toward increasing the intake of natural antioxidants,
of NFκB.119 Resveratrol is an antioxidant agent derivative of especially in the geriatric population.2,125 Many antioxidant
stilbene, which passed unnoticed until it was related to the vegetables and fruits have been identified such as potato,
French paradox.118 The “French paradox” is a term generated spinach, tomatoes, and legumes or berries, cherries, citrus,
in 1992 based on epidemiological data from French people prunes, and olives.2,126 Interestingly, melatonin is a powerful
who had a low incidence of CVDs despite the high consump- cardioprotective agent and has shown beneficial effects
tion of saturated fat. This paradox was attributed to their high on cardiac aging and many other age-related disorders.125
wine consumption (20–30 g/day), which was suggested to Melatonin (N-acetyl-5-methoxytryptamine) is an endog-
decrease platelet aggregation.120 Since 1992, the French para- enously produced indoleamine synthesized from the essential
dox has considerably evolved, and its explanation has been amino acid tryptophan and secreted by the pineal gland in
attributed to resveratrol beneficial effects because it a circadian manner, but also by extrapineal organs (ie, gas-
• reduces vascular remodeling and inflammation, reducing trointestinal tract, immune system cells, retina, spleen, liver,
vascular smooth muscle cells proliferation, vascular kidney, and heart) not in a circadian manner.127,128 Melatonin
calcification, and interfering with the expression of has also been identified in a very large number of plant spe-
proinflammatory enzymes;118 cies, in plant food and medical herbs. In particular, among
• prevents endothelial dysfunction increasing the expres- the plant products in which melatonin has been identified, the
sion of NOS and vascular dilation, contributing also to most important are diet products including wine, olive oil,
the prevention of hypertension;121 tomato, and beer.125 Melatonin acts through several mecha-
• reduces platelet recruitment and aggregation;122 nisms: directly scavenging free radicals and indirectly upreg-
• reduces LDL oxidation and LDL and triglycerides ulating antioxidant enzymes and downregulating prooxidant
levels;118 enzymes.129 Aging is associated with a significant reduction
• improves glucose metabolism by increasing insulin sensi- in endogenous melatonin secretion, resulting in an augmen-
tivity and glucose absorption mediated by glucose trans- tation of oxidative stress and other metabolic changes.130
porter-4 and protecting pancreatic β-cells function.123 Melatonin receptors have been identified in the human CV
These effects are positively related to the reduction of system, mainly localized in the ventricular wall, coronary
CVDs. However, wine and/or resveratrol can also reduce the arteries, aorta, and peripheral arteries, where they exert a

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protective effect from serious CV events, such as ischemic especially intensity.137 The relationship between exercise
heart disease, acute myocardial infarction, and also cardiac intensity and oxidative stress adaptation in older adults shows
syndrome X, an angina-like chest discomfort.125 In particular, that both inactivity and high-intensity physical exercise
some authors have observed an antihypertensive effect of the are related to increased oxidative stress, whereas moderate
melatonin, administered orally at 1.5 mg each day, on elderly intensity exercise is related to a reduction in oxidative stress
hypertensive volunteers of both genders (63–91 years old), levels.136 In fact, physical exercise training can be divided into
hypothesizing as a possible explanation that melatonin binds acute, endurance, and resistance. In particular, acute exer-
to peripheral receptors in the arteries inducing vasodilatation cise induces increased production of free radicals in elderly
followed by a decrease in arterial blood pressure.131 Mela- subjects, together with an increase in antioxidant defenses
tonin also shows a protective effect from cardiac ischemia- which, given its age-related decline, seems to be ineffec-
reperfusion (RI)-induced infarction.132 Furthermore, a recent tive in neutralizing all of the free radicals produced during
study showed that the oral administration of melatonin in exercise, setting up a status of oxidative stress.138–140 On the
patients who were undergoing elective coronary artery bypass other hand, endurance training induces both a decrease in
grafting could ameliorate, in a dose-dependent way (10 mg the production of free radicals and an increase in antioxidant
capsule vs 20 mg capsule once daily), myocardial RI injury by defenses in elderly people. According to the findings in the
interfering with the oxidative stress, inflammation, and apop- literature, optimal aerobic training for oxidative/antioxidant
totic markers.133 Melatonin may show a protective effect also balance effects can be achieved with intensities between
from myocardial infarction but, at the present time, only two 50% and 80% of VO2max (the maximum rate of oxygen
clinical trials, the MARIA and the IMPACT, are currently consumption measured during incremental exercise) and
investigating the effects of melatonin in patients at high risk with a frequency of two to three sessions per week.136 At the
of acute myocardial infarction.125 In the MARIA trial, patients same time, resistance training improves antioxidant defenses
undergoing revascularization for ST-elevation myocardial in elderly population.141 This effect can be achieved by train-
infarction (STEMI) received intravenous (51.7 μmol) and ing protocols provided of sufficient volume for each muscle
intracoronary (8.6 μmol) melatonin immediately before and group (3–5 sets, 10 repetitions) and intensities between 50%
during percutaneous coronary intervention (PCI);134 whereas, and 80 % of one-repetition maximum, the maximum amount
in the IMPACT trial, acute myocardial infarction patients will of force that can be generated in one maximal contraction.136
receive an intracoronary (1 mg) and intravenous (49 mg) dose The role of oxidative stress in age-related sarcopenia suggests
of melatonin.135 In particular, the MARIA trial has showed the importance of physical activity in limiting this process in
that, when administered via intravenous and intracoronary elderly subjects and its association with increased RONS
during primary PCI for STEMI, melatonin had an accept- generation, but it can also induce an increase in antioxidants
able safety and tolerability profile, but it did not appear to defense, positively affecting oxidative/antioxidant balance,
exert a significant effect on myocardial infarct size measured if a moderate intensity protocol of endurance or resistance
by magnetic resonance imaging (MRI) and it may have a training is chosen, avoiding acute one.142
detrimental effect after STEMI, mainly because it might
facilitate left ventricular remodeling.134 Given its cardiopro- Conclusion
tective effects and safety, increased blood melatonin levels RONS are produced by several endogenous and exogenous
could be obtained by moderate and chronic consumption of processes. Oxidative stress results from the imbalance
wine, beer, walnuts, and other food or beverages that contain between RONS production and antioxidants defense and
melatonin, but further investigations are needed to expand its is primarily involved in “aging theory”, in particular in the
range of applications and also to better understand its specific “oxi-inflamm-aging hypothesis”. Oxidative stress is also
mechanism(s) to improve CV physiology.125 related to several chronic diseases and, together with chronic
inflammation, to sarcopenia and frailty in elderly population.
Physical exercise Biomarkers of oxidative stress may be useful as diagnostic
Inactivity and aging are known to increase basal RONS tool or therapeutic target. Antioxidant therapy, such as
concentrations in skeletal muscle, leading to sarcopenia.136 In resveratrol and other nutritional compounds, together with
contrast, regular physical activity is an important determinant moderate aerobic exercise, may positively affect the clinical
in maintaining an optimal state of health, reducing oxidative damage induced by oxidative stress. Further investigations
stress and preventing chronic diseases, but these beneficial are needed to evaluate the real efficacy of these therapeutic
effects are related to the features of physical exercise, interventions.

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Disclosure 26. Gradinaru D, Borsa C, Ionescu C, Prada GI. Oxidized LDL and NO
synthesis – biomarkers of endothelial dysfunction and ageing. Mech
The authors report no conflicts of interest in this work. Ageing Dev. 2015;151:101–113.
27. Brinkley TE, Nicklas BJ, Kanaya AM, et al. Plasma oxidized low-density
lipoprotein levels and arterial stiffness in older adults: the health, aging,
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Oxidative stress, aging, and diseases

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Figure 1 Oxidative stress, age-related diseases, and relative biomarkers.

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accumulation is thought to be a common determinant in the $JLQJ

used as biomarkers of oxidative stress, such as the nitration

mass quantity.3 On the other hand, several mechanisms,

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Table 1 Overview of the most important oxidative stress biomarkers

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AGEs levels, and in the elderly, AGEs levels positively  

correlate with lipid profiles and atherosclerotic char-

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AGEs levels, and in the elderly, AGEs levels positively