G Model

MAD-10703; No. of Pages 21

Mechanisms of Ageing and Development xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

Micronutrient–gene interactions related to inflammatory/immune

response and antioxidant activity in ageing and inflammation.
A systematic review
Eugenio Mocchegiani a,*, Laura Costarelli a, Robertina Giacconi a, Marco Malavolta a,
Andrea Basso a, Francesco Piacenza a, Rita Ostan b, Elisa Cevenini b, Efstathios S. Gonos c,
Daniela Monti d
a
Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8,
60121 Ancona, Italy
b
Department of Experimental Diagnostic and Specialty Medicine (DIMES) and Interdepartmental Centre ‘‘L. Galvani’’ (CIG), University of Bologna, Via San
Giacomo, 12, 40126 Bologna, Italy
c
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece
d
Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy

A R T I C L E I N F O A B S T R A C T

Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory
content of some micronutrients within the cells maintain several immune functions, a low grade of
Article history:
Available online xxx inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal
role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as
in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks.
Keywords:
Zinc/copper/selenium–gene interactions Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis,
Immune system such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders.
Antioxidant activity Moreover, the genetic inter-individual variability may affect the nutrients’ absorption (nutrigenetic)
Ageing with altered effects on inflammatory/immune response and antioxidant activity. The interaction
Longevity between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence
ageing and longevity because the micronutrients may become also toxic. This review reports the
micronutrient–gene interactions in ageing and their impact on the healthy state with a focus on the
method of protein–metal speciation analysis. The association between micronutrient–gene interactions
and the protein–metal speciation analysis can give a complete picture for a personalized nutrient
supplementation or chelation in order to reach healthy ageing and longevity.
ß 2013 Published by Elsevier Ireland Ltd.

1. Introduction As a result, the ‘‘remodelling theory of ageing’’ has been proposed

Ageing is an inevitable biological process that is accompanied
by gradual and spontaneous biochemical and physiological
changes including increased susceptibility to diseases, adverse
environmental conditions and loss of mobility and agility.
Alterations in the neuroendocrine–immune interactions as well
as in the antioxidant capacity also play a fundamental role in
ageing. The inability of an organism in coping with these changes
may lead to the onset of some degenerative age-related diseases.
* Corresponding author at: Scientific and Technological Pole INRCA-IRCCS,
Translation Center of Research in Nutrition and Ageing, Via Birarelli 8, 60121
Ancona, Italy. Tel.: +39 0718004216; fax: +39 071206791.
E-mail address: e.mocchegiani@inrca.it (E. Mocchegiani).
(Paolisso et al., 2000). Various nutritional factors are directly linked
with these phenomena as for instance in restoring neuroendo-
crine-immune network, the metabolic harmony and the capacity
to respond to oxidative stress (Meydani, 2001). Approximately, 40
micronutrients (vitamins, essential minerals and other compounds
required in small amount for normal metabolism) have been
reported as essential components of the diet (Alvarez Leon et al.,
2006). The dietary intake of essential micronutrients is often
inadequate in the elderly due to several causes (Ames, 2006). First
of all, the poor socio-economic condition present in a large part of
old people may lead to a consumption of inexpensive foods
deficient in micronutrients, such as carbohydrates (Kant, 2000).
The gap is worsened by loss of appetite, lack of teeth, intestinal
malabsorption and decreased requirement of energy that lead, as a
final result, to frailty, disability and mortality (Semba et al., 2006).

0047-6374/$ – see front matter ß 2013 Published by Elsevier Ireland Ltd.

http://dx.doi.org/10.1016/j.mad.2013.12.007

Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
G Model
MAD-10703; No. of Pages 21
2 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Some authors have reported that the deficiency of micronutrients
in ageing is strictly related to global impairments of the immune
functions, metabolic harmony and antioxidant defence by external
noxae with subsequent onset of age-related diseases (Failla, 2003).
Indeed, many micronutrients contribute directly or indirectly to
the biological activity of some antioxidant enzymes (superoxide
dismutase, SOD; glutathione peroxidase, GPx; catalase), to the
efficiency of the immune system, to the metabolic harmony, to
keep under control the inflammatory state and, as such, to
maintain the correct functioning of many body homeostatic
mechanisms with subsequent achievement of the longevity
(Mocchegiani et al., 2008c) and, finally, to the maintenance of
metabolic function especially in preventing mitochondrial decay
(Ames, 2006). In this last context, feeding studies in old rats have
shown that mitochondrial metabolites and antioxidants protect
the neuronal cells from neurotoxin- and oxidant-induced toxicity
and oxidative damage but especially they delay the normal
senescence of human diploid fibroblasts and the oxidant-induced
senescence (Liu et al., 2002). With advancing age, an increased
oxidative damage to proteins and lipid membranes, particularly in
mitochondria, causes a deformation of the structure of enzymes,
with a consequent decrease of enzyme activity as well as substrate
binding affinity for their substrates. An increased level of substrate
by micronutrients restores the speed of the reaction as well as
mitochondrial function, thus delaying mitochondrial decay and
ageing (Liu et al., 2002). In contrast, recent longitudinal studies in
dietary daily intake in human nonagenarians/centenarians (suc-
cessful ageing) have shown that an adequate consumption of
micronutrients as well as a satisfactory content of some trace
elements within the cells lead to good performances in several
immune functions, to metabolic compensation and preservation of
the antioxidant activity (Chernoff, 2001). In this context, polyun-
saturated fatty acids, highly sensitive to reactive oxygen species
(ROS), decrease in liver mitochondria from human centenarians, a
feature that could represent a protective mechanism to favour
longevity (Anantharaju et al., 2002). Therefore, nutritional factors
can play a pivotal role for healthy ageing and longevity. However,
the effects of the nutrients are strongly influenced by genetic
factors, in particular by genes involved in inflammatory/immune
response and antioxidant activity. The genes of IL-1, IL-6, TNF-a
pro-inflammatory cytokines, of IL-10 anti-inflammatory cytokine,
of HSP70 chaperone and the regulators of trace elements
homeostasis, Metallothioneins (MT), seem particularly relevant
because they are involved in the susceptibility to major geriatric
disorders, such as diabetes, osteoporosis, osteoarthritis, dementia,
cardiovascular diseases (CVD) and infections (Franceschi, 2007;
Mocchegiani et al., 2006a,b). Indeed, up to 25% of the variation in
human lifespan is heritable (Mitchell et al., 2001); the rest is due to
environmental and life style factors, which impact on the ageing
process contributing, as such, to a large inter-individual variability.
Therefore, current problems are to understand how the interaction
between genetic factors and nutrients may influence the ageing
process and longevity in view of the high impact of gene
expression, protein production and epigenetic mechanisms in
regulating the life span (Mattson, 2008). Some dietary patterns
fave shown very different impact on long-term disease occurrence
and survival. In this context, a strong evidence for a beneficial
effect of higher compliance to the ‘‘Mediterranean’’ dietary pattern
on causes of death, including those ones by CVD and cancer, has
been reported (Mitrou et al., 2007). Anyway, it is also commonly
accepted that the complex interactions of multiple polymorphisms
play a key role in how individuals may respond to dietary
interventions (nutrigenetic approach) or how some nutrients may
affect the gene expressions (nutrigenomic approach) (Darton-Hill
et al., 2004). For each nutrient, there is a window of intake between
the Recommended Dietary Allowance (RDA), (defined as the
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
dietary intake sufficient to meet the requirement of 97% of healthy
individuals in a particular stage of the life and gender group), and
the tolerable upper limit (UL), which is the highest nutrient intake
that can be achieved without incurring risk of adverse health
effects for most individuals in the general population (Stover,
2006). Although worldwide research on genetic variation that
requires a different RDA or UL is still in progress, several genes and
alleles have been suggested to affect nutrient utilizations
(Mocchegiani et al., 2012a). During this last decade, it has been
recognized the pivotal role played by some micronutrients (zinc,
copper, selenium) in maintaining the correct functioning of many
body homeostatic mechanisms with subsequent achievement of
longevity (Mocchegiani et al., 2008c). Taking into account the
influence of these nutrients in many genes involved in inflamma-
tory/immune response and antioxidant activity (Mocchegiani
et al., 2012a), the micronutrient–gene interactions are fundamen-
tal to escape many age-related diseases and to achieve healthy
longevity. We report the specific role played by the most relevant
micronutrient–gene interactions in ageing with a focus on the
precise determination of their specific transporter proteins, by
means of the method of protein–metal speciation analysis
(Malavolta et al., 2012). As such, the association between
micronutrient–gene interactions and protein–metal speciation
analysis may give a complete picture of the personalized
micronutrient supplementation or chelation (in the case of
nutrient overload) in order to reach healthy ageing and longevity.
2. Micronutrients, immune efficiency, antioxidant response,
ageing
2.1. Zinc, immunity, antioxidant response and ageing
Zinc (Zn) is an essential micronutrient required for many
cellular processes, including the correct function of the immune
system and antioxidant response. Zinc homeostasis and signaling,
acting as a ‘‘second messenger’’, are both critical in immune
activation and against oxidative stress (Powell, 2000; Chasapis
et al., 2012). An imbalance in zinc homeostasis is associated with
the development of chronic diseases. Zinc deficiency (genetic or
nutritional) causes significant impairment in both adaptive and
innate immune responses, promotes systemic inflammation and
impaired antioxidant defence (Fraker and King, 2004; Chasapis
et al., 2012; Wong and Ho, 2012). A plethora of data indicates that a
significant portion of the aged population has inadequate zinc
intake with a decline in zinc state with advancing age (Mocche-
giani et al., 2013b).
Zinc deficiency in the elderly seems to be due to many factors
related to the ageing process, such as inadequate mastication and
psychosocial factors leading to a reduction of zinc-rich foods
(bovine, ovine and pork meat, hard cheese, nuts, cocoa, eggs)
intake, altered intestinal absorption, alteration in zinc transporter
proteins, drug interactions and competition between zinc and
other bivalent minerals (copper, iron, calcium and selenium) or
vitamins (Mocchegiani et al., 2013b). The intracellular zinc
homeostasis is regulated by buffering Metallothioneins (MT), i.e.
the major storage proteins for zinc, and by zinc transporters (ZnT
and ZIP families) for cellular zinc efflux and influx, respectively,
that mediate the intracellular zinc signaling. The main reasons why
intracellular zinc levels are compromised during ageing have been
traced to the increased expression of MT (Mocchegiani et al., 2007)
and to the defective zinc transporters, which could result in
increased sequestration of zinc and low intracellular free zinc
content (Mocchegiani et al., 2013b). Specifically, MT preferentially
bind zinc but in ageing they are unable to release zinc in order to be
used by other Zn-dependent antioxidant enzymes and proteins
related to the efficiency of the immune system. Indeed, zinc, acting
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
as a ‘‘second messenger’’, modulates the signaling cascades that
improve antioxidant and immune defenses, such as the activation
of Nrf-2 transcription factor as well as a zinc-finger protein A20,
which inhibits Nuclear Factor Kappa B (NF-kB) activation via TRAF
pathway (Prasad, 2008). Consequently, the zinc release from
proteins acts both as antioxidant and anti-inflammatory agent.
Therefore, the low free zinc ion availability and the high MT levels
result in the failure of the antioxidant and immune response
provoking increased inflammation followed by infection relapses
in the elderly (Mocchegiani et al., 2000a,b, 2003). The major
alterations of a zinc deficiency are the involution of the thymus,
defective lymphocytes maturation and function, decline in both
cellular and humoral immune response (Haase and Rink, 2009a,b)
and the maintenance of a systemic low grade of chronic
inflammation (named ‘‘inflammaging’’) (Franceschi et al., 2000).
These alterations can lead to an increased risk for the onset of
degenerative age-related diseases (Mocchegiani et al., 2013b). The
thymic involution is due to enhanced apoptosis of lymphocyte
precursors (Fraker and King, 2001) and to a reduction of the
activity of thymulin (Prasad et al., 1988): an hormone secreted by
thymic epithelial cells requiring zinc as a cofactor for thymulin
biological activity and essential for the differentiation, maturation
and function of T cells. As a consequence, the thymic output
(measured using T cell receptor rearrangement excision circles) is
reduced during ageing leading to a substantial loss of pre-T cells
and a reduced number of naive mature T cells in the circulation
with subsequent inability to substitute activated memory T cells
that undergo to apoptosis after exposure to ‘‘foreign’’ antigens
(Mitchell et al., 2006). Centenarians display satisfactory zinc pool
(Mocchegiani et al., 2003) and a sufficient maintenance of the
thymic output by IL-7 (Nasi et al., 2006). IL-7 and its receptor act
via zinc finger protein Miz-1 and SOCS1 (Saba et al., 2011), which is
in turn regulated by another zinc finger protein TRIM8/GERP
(Toniato et al., 2002).
Moreover, zinc deficiency is accompanied by reduced T cell
proliferation upon mitogen stimulation, reduced precursor num-
ber and activity of CD8 cytotoxic T cells, and impaired CD4 helper T
cell functions, resulting in an imbalance of Th1/Th2 cytokines
secretion (Beck et al., 1997; Uciechowski et al., 2008), character-
ized by decreased IFN-g, IL-2 and TNF-a production by Th1 cells
and increased IL-6 production by Th2 cells and macrophages,
similarly to what occurs at old age in CD4T lymphocytes (Alberti
et al., 2006). In vitro, zinc supplementation can modulate T cell-
dependent immune reactions, for example by leading to cytokines-
mediated T cell activation, but higher concentrations of zinc can
directly suppress T cell function by reducing IL-1-dependent T cell
stimulation through the inhibition of interleukin-1 receptor
associated kinase-1 (Wellinghausen et al., 1997).
The absolute low number of mature B cells in ageing is not
affected by zinc deficiency. However, low zinc levels cause a
reduction in B cell lymphopoiesis resulting in decreased number of
pre-B and immature B cells due to accelerated apoptosis and
impaired antibody response, particularly against T cell-dependent
antigens (Moulder and Steward, 1989).
Zinc deficiency also affects the functions of cells involved in
innate immune response. For example, zinc deficiency reduces the
lytic activity of NK cells (Haase and Rink, 2009b), impairs NKT cell
cytotoxicity and immune signaling (Mocchegiani et al., 2009),
decreases the chemotaxis and oxidative burst by neutrophils
(Moroni et al., 2005), inhibits mast cell activation (Kabu et al.,
2006) contributing to the higher incidence of viral infections and
cancer typical of the elderly. Indeed, zinc supply plays a relevant
role in restoring NK cell function in elderly (Mocchegiani et al.,
2003). Both zinc and MT affect NKT cell development, maturation
and function (Mocchegiani et al., 2009). In conditions of chronic
stress, including ageing, the zinc release by MT is limited, leading
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
3
to low intracellular zinc bioavailability and subsequent reduced
innate immunity (Mocchegiani et al., 2006a,b). Additionally, a zinc
finger motif [Krüppel-like factor 2 (Kfl2] plays an important role in
the immune response of gdNKT cells (Odumade et al., 2010). In
zinc deficiency, gdNKT cell cytotoxicity and Kfl2 activity are
impaired (Mocchegiani et al., 2009). The mechanism by which zinc
may affect the adaptive and innate immunity is by targeting NF-kB,
a transcriptional regulatory factor of proinflammatory responses
(Hayden and Ghosh, 2008). In dietary zinc deficiency, in ageing or
in depletion of intracellular zinc with a zinc-specific chelator, NF-
kB activation increases with subsequent proinflammatory cyto-
kine gene expressions and production leading to the appearance of
chronic inflammation coupled with some age-related degenerative
diseases (Bao et al., 2010; Golovine et al., 2008; Mocchegiani et al.,
2013b). In humans, zinc supplementation improves the immune
functions and decreases the inflammation (Mocchegiani et al.,
2013b). Zinc supplementation in the elderly reduces the incidence
of infections (Prasad et al., 2007), increases delayed-type
hypersensitivity (DTH) reaction (Duchateau et al., 1981) and
enhances the T cell function (Cossack, 1989). Moreover, the age-
related increase in proinflammatory markers (C-reactive protein
and inflammatory cytokines) are restored by zinc supplementation
(Bao et al., 2010). Zinc is also involved in the wound healing
process occurring concomitantly to the inflammatory response by
conferring resistance to epithelial apoptosis through the cytopro-
tection against reactive oxygen species (ROS) and bacterial toxins,
probably thanks to the antioxidant activity of MT (Lansdown et al.,
2007).
On the whole, since zinc deficiency may affect the immune
functions and antioxidant activity, many studies have been
performed to evaluate the effect of zinc supplementation in
elderly with contradictory results (Haase and Rink, 2009a,b;
Mocchegiani et al., 2013b). In elderly and in old infected patients
(Mocchegiani et al., 2003; Kahmann et al., 2008), as well as in an
accelerated ageing condition, such as Down’s syndrome (Fran-
ceschi et al., 1988), zinc treatment improves the thymic endocrine
activity, the lymphocyte mitogen proliferative response, CD4T cell
number, Th1/Th2 ratio, NK cell cytotoxicity and reduces the
spontaneous release of inflammatory cytokines. Moreover, zinc
supplementation improves DNA repair (Chiricolo et al., 1993) and
increases the gene expressions of some zinc transporters (ZIP 1)
(Andree et al., 2004), leading to the correct maintenance of the
intracellular zinc homeostasis and to significant clinical reductions
of relapsing infections.
It is advised to supplement zinc at physiological doses (RDA:
10–12 mg zinc/day) for short periods (1 month) at alternating
cycles. These doses of zinc maintain a correct balance among
minerals (copper and iron), which closely interact (Mocchegiani
et al., 2012a). However, the accumulation of zinc may become toxic
and it may lead to an abnormal activation of some zinc-dependent
enzymes, such as PARP-1 involved in genomic stability, or favour
the entering of excessive calcium into the cells, with subsequent
cell death in both cases (Mocchegiani et al., 2000b; Frazzini et al.,
2006). It should be noted that the genetic background may also
influence an individual’s response to zinc supplementation. Recent
studies showed that polymorphisms in IL-6 174G/C and in MT1A
+647A/C loci impact on the effect of zinc supplementation upon the
immune and antioxidant response in the elderly (Mocchegiani
et al., 2012a, 2013b; Mariani et al., 2008b), as discussed below in
details (Section 3.1.1).
2.2. Copper, immunity, antioxidant response and ageing
Copper (Cu) is a trace element/micromineral bound to proteins,
80–90% to ceruloplasmin (Cp). Copper is important for the
development and maintenance of the immune system, in
G Model
MAD-10703; No. of Pages 21
4 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
particular of neutrophil and monocyte functions even if its role is
still controversial/ambiguous in immunity (Maggini et al., 2007).
Copper is also essential for an optimal antioxidant defense, as it
functions as a cofactor of Cu–zinc superoxidase dismutase (Cu, Zn–
SOD): an enzyme important for free radical eradication (Prohaska
and Gybina, 2004). Thus, copper deficiency may compromise
cellular antioxidant defenses via decreased capability to produce
SOD, thereby increasing their susceptibility to oxidative DNA
damage and, consequently, also the efficiency of the immune cells
(Pan and Loo, 2000).
The actual estimated dietary allowances for adults lie between
1 and 1.5 mg/day. Copper deficiency is not very common in human.
However, some studies report that plasma copper levels are
elevated during ageing strictly dependent by the dietary habits
(Madarić et al., 1994), leading to a concomitant augment of serum
Cp and cytochrome-c oxidase activity in platelets (Linder and
Hazegh-Azam, 1996). The increase in copper might heighten the
rate of lipid peroxidation through enhanced formation of free
radicals with the consequent impairment of the immune response
(Mukhopadhyay et al., 1997). Anyway, the role of copper has to be
considered together with others minerals, such as zinc, since
copper displays its biological function by bounding MT even more
tightly than zinc. This bound-copper becomes unavailable for
transfer out of the cell thereby decreasing zinc absorption (Cousins,
1985). Associations between plasma copper and zinc levels and the
health state have been reported in the elderly. In particular, plasma
Cu/Zn ratio, higher in women than men and increased with
advancing age, was associated with inflammatory (CRP, IL-6) and
nutritional (serum albumin) markers, and with predicted 3.5 years
mortality over 70 years of age (Mocchegiani et al., 2012b). Higher
plasma Cu/Zn ratio was also reported in subjects with stable
cardiovascular disease (CVD), mainly due to increased plasma Cu
(Malavolta et al., 2010). However, most of the age-related changes
of Cu/Zn seemed to result from a progressive decline of plasma
zinc. Indeed, zinc supplementation ameliorates abnormally high
plasma Cu/Zn ratio in old hemodialysis patients improving the
inflammatory (IL-6) and immune state (CD4/CD8 ratio) (Guo and
Wang, 2013). Consequently, Cu/Zn ratio may be considered as an
important clinical inflammatory-nutritional biomarker and a
significant predictor of all-cause mortality in over 70-year-olds
(Mocchegiani et al., 2012b).
Ageing does not modify significantly copper metabolism and
dietary copper intake of elderly people seems to be adequate.
Therefore supplementation of copper is in general not necessary
and no recent clinical studies are available where copper, as a
single micronutrient, was therapeutically given to elderly people
especially in relation to the immune functions (Muñoz et al., 2007).
Some studies were carried out in some age-related neurogenera-
tive diseases (Parkinson, Huntington’s disease, Alzheimer’s de-
mentia) in relation to the immune functions, but whether copper
dysregulation is a cause or a consequence of altered immune
functions in these neurodegenerative diseases is under investiga-
tion (Festa and Thiele, 2011).
With regard to antioxidant response few studies exist in ageing.
The effect of copper supplementation on oxidative stress and life
span was assayed in superoxide dismutase (SOD) mutants
Saccharomyces cerevisiae. Copper supplementation increased the
lifespan of the SOD1 and SOD2 mutants, indicating that copper
supplementation increases longevity by reducing or removing the
superoxide production, via increased gene expression of metal-
lothionein Cup1 (Kirchman and Botta, 2007). However, copper,
being a redox-active transition metal, may initiate repetitive
radical formation through redox cycling (Lalioti et al., 2009).
Therefore, excessive copper can cause increased oxidative
damage to lipids, proteins and DNA and contributes to the onset
of neurodegenerative and age-related disorders (Linder and
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
Hazegh-Azam, 1996). Furthermore, excessive copper directly
participates in peroxidation of membrane lipids (Chow, 1979;
Powell, 2000) impairing the cellular membrane function, which
can be prevented by some ROS scavengers (Mattie and Freedman,
2001)
2.3. Selenium, immunity, antioxidant response and ageing
Selenium (Se) is a trace element in the organism representing
an essential component of selenoproteins that play an important
role in many biological processes, including adaptative and innate
immune responses and antioxidant defense (Behne et al., 1998;
Kryukov et al., 2003). In humans 25 genes encode for selenopro-
teins, such as glutathione peroxidases (GPx), the plasma Se-
transport protein selenoprotein P (SePP) and thioredoxin reduc-
tases (TrxR) (Kryukov et al., 2003). These selenioproteins, by
participating in the reduction of hydrogen peroxide and lipoper-
oxide, regulate the oxidative stress (Papp et al., 2007). SNPs (single
nucleotide polymorphisms) in the selenoprotein genes can
modulate the function of selenoproteins, thus affecting the cellular
response to oxidative stress (Meplan, 2011).
Ageing is characterized by selenium inadequacy due to a
reduced intake of protein dense food, such as red meat (Arnaud
et al., 2007). The Epidemiology of Vascular Ageing (EVA) study has
shown that people with low plasma selenium at the baseline are
susceptible to mortality by cancer (Akbaraly et al., 2005), display
cognitive decline (Akbaraly et al., 2007) and dysglycemia (Akbaraly
et al., 2010). Furthermore, transcriptomics and proteomics
approaches have revealed that the variation in selenium state
influences different cellular pathways, such as mTOR pathway,
which are proposed to be correlated with the ageing process and
age-related diseases (Kipp et al., 2009). The mTOR pathway is
involved in cell senescence where MT play also a crucial role as
antioxidant agent (Mocchegiani et al., 2013a) suggesting a close
interrelationship among mTOR, selenium and MT against oxidative
stress and cellular senescence. Therefore, selenium supplementa-
tion may be useful to prevent, other than oxidative stress, also
cellular senescence (Pagmantidis et al., 2008).
With regard to the immune efficiency, Se stimulates the
antibody formation, the activity of helper and cytotoxic T cell and
NK cells (Mehdi et al., 2013). ‘‘In vitro’’ and ‘‘in vivo’’ animal studies
showed that glutathione peroxidase and other selenoproteins,
such as thioredoxin reductase (TrxR) and methionine sulfoxide
reductase (Msr), play key roles in regulating the concentration of
peroxide and other oxidant compounds in the microenviroment of
the immune cells. In fact, selenium reduces oxidized MT through
glutathione peroxidase with subsequent zinc release by MT, with a
final result in the activation of some antioxidant zinc-dependent
enzymes and subsequent benefits in maintaining the integrity of
the immune cells (Maret, 2003). Indeed during ageing, some
fundamental functions of leukocytes, such as activation, prolifera-
tion, differentiation and phagocytosis, may be compromised by the
increased oxidative damage resulting from continuous production
of ROS due to selenium deficiency (Rayman, 2012).
A supplementation of selenium (100 mg/day) for 6 months in
institutionalized elderly individuals leads to an increment in
serum selenium levels and to an improvement of the proliferative
response to pokeweed mitogen (Peretz et al., 1991). In addition, a
daily low dose supplementation of zinc and selenium (20 mg
zinc + 100 mg selenium) for two years in institutionalized elderly
people increased the antibody titers after influenza vaccine and
contributed to a significant improvement of the immunological
parameters and infection rates (Girodon et al., 1999). Another
study showed that a supplementation with selenium (400 mg/day)
for 6 months in healthy old humans increased of more than 50% the
percentage of CD4+ T cells. Interestingly, also the NK cell-mediated
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
cytotoxicity was enhanced after 3 months of Se-supplementation
(Wood et al., 2000). Moreover, a satisfactory serum selenium
concentration was positively associated with good peripheral
CD16+ NK cell numbers in healthy free-living nonagenarians
(Ravaglia et al., 2000). Selenium ‘‘in vitro’’ enhanced the
chemotaxis, phagocytic functions and MCP-1 synthesis by
peripheral blood mononuclear cells (PBMCs) from old subjects
(Ventura et al., 1994). Of interest is the existence of an inverse
correlation between serum selenium and IL-6. Old subjects with
the lowest selenium levels display high IL-6 levels coupled with an
higher risk of mortality over a period of 5 years, with thus a close
relationship between selenium state and inflammation mediated
by IL-6 in elderly (Walston et al., 2006). Overall, selenium state is
generally perceived as an important factor for maintaining the
health in the elderly (Gonzalez et al., 2007; Ray et al., 2006), even if
the mechanisms by which Se-supplementation may improve
immune and antioxidant responses in old individuals have not
been fully elucidated yet. The selenium–gene interactions may
clarify this point (see below Section 3.3).
3. Micronutrients and gene interactions
During this last decade the pivotal role played by some
micronutrients (zinc, copper and selenium) in maintaining the
correct functioning of many body homeostatic mechanisms with
subsequent achievement of the longevity emerged (Mocchegiani
and Malavolta, 2008b; Mocchegiani et al., 2008c). Taking into
account the influence of these nutrients in many genes involved in
inflammatory/immune response and antioxidant activity (Moc-
chegiani et al., 2012a), the micronutrient–gene interactions are
fundamental to escape many age-related diseases and to achieve
the longevity in healthy state through a personalized diet
containing these specific nutrients. In this section, we report the
specific role played by the most relevant micronutrient–gene
interactions in ageing with an extension on their deficiency or
toxicosis in order to choose a personalized nutrient supplementa-
tion or chelation, respectively.
3.1. Zinc and gene interactions
Zinc plays a key role for many biological functions because of its
occurrence in over one thousand enzymes as a catalytic ion and in
at least the same number of proteins as a structural metal (Maret,
2006; Andreini and Bertini, 2012). Such a role is strengthen by the
role of zinc in the processes of genetic stability and gene
expression, taking into account that about 25% of the cellular zinc
content is in the nucleus (Cousins, 1998). Mutations in some genes
coding for zinc-related proteins are the basis for inborn errors of
zinc metabolism, as it occurs in acrodermatitis enteropathica, a
rare disorder with a mutation in the Zip4 (SLC39A4) importer gene
and resulting in severe zinc deficiency (Kury et al., 2002).
Furthermore, the risk of type II diabetes in ageing has been
associated with a single nucleotide polymorphism (SNP) resulting
in an Trp325Arg substitution in the pancreatic b-cell-specific zinc
transporter protein ZnT-8 (SLC30A8), which provides zinc for
insulin maturation and/or storage (Sladek et al., 2007). Moreover, a
novel Zip2 Gln/Arg/Leu codon 2 polymorphism is associated with
carotid artery disease in ageing (Giacconi et al., 2008b). These
findings clearly suggest that zinc, through zinc transporters, may
affect the genetic stability with subsequent altered modifications
of the zinc homeostasis and metabolism. Such an assumption is
supported by the fact that zinc, via zinc fingers, is involved in DNA
replication of many proteins essential for cell proliferation, cell
differentiation, cell growth arrest, cell division, signal transmis-
sion, growth factors production, protoncogenes activation, che-
mokine production, and for codifying hormone nuclear receptor
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
5
superfamily and for nuclear transcription factor activation (Klug,
1999; Mackay and Crossley, 1998). Indeed, the zinc finger motifs
regulate the gene expression of a large number of genes encoding
metallo-regulatory proteins and acting as ‘‘zinc sensors’’ for many
transcriptional factors with also an autoregulatory mechanism
(Lyons et al., 2000). This is the case of some regulatory or inhibitory
transcription factors (Egr-1, Sp1, A20), which, together with other
zinc-regulated transcription factors (NF-kB, STAT, HSF-1, Kruppel
zinc finger family), are involved in the regulation of the gene
transcription of pro-inflammatory cytokines (IL-6, TNF-a) and heat
shock protein (Hsp70) in presence of antigenic stimuli (Rink and
Kirchner, 2000). Of interest, it is the Kruppel zinc-finger family
because implicated as transcriptional factors in many biological
processes, including proliferation, apoptosis, differentiation, de-
velopment and in controlling the inflammatory/immune response
and oxidative stress (Pearson et al., 2008). The characteristic of this
family is the presence of three Kruppel-like zinc fingers, which
bind to CACCC elements and GC-rich regions of DNA, to mediate
activation and/or repression of transcription. Within of this family,
a peculiar role is played by Klf2 because involved in T cell
proliferation as well as in controlling the IFN-g and TNF-a
production, via NF-kB (Das et al., 2006), and consequently the
inflammatory state. On the other hand, mutant mice lacking Kfl2
(ZFP36) showed signs of severe generalized inflammation caused
by overproduction of TNF-a (Pearson et al., 2008). Of interest is
also the Kfl5 because affecting the nuclear enzyme PARP-1
(Swamynathan, 2010), which is involved DNA-repair during
oxidative stress and inflammation in ageing and in age-related
diseases (Mocchegiani et al., 2000b). The lack of zinc in these last
conditions provokes a reduced activity of PARP-1 with subsequent
no DNA-repair, as it instead occurs in centenarians showing good
PARP-1 activity, reduced inflammation and satisfactory intracel-
lular zinc ion bioavailability (Mocchegiani et al., 2003). Therefore,
zinc finger proteins are indispensable to transduce the signal from
the cytokine receptors into expression of response genes and,
consequently, in maintaining a correct balance of Th1/Th2
paradigm. In the course of zinc deficiency, an unbalance of Th1/
Th2 paradigm appears with a shift towards Th2 cells and chronic
inflammation (Prasad, 2000). Other than zinc finger proteins, zinc
also affects a wide range of genes involved in metabolism,
oxidative stress and inflammatory/immune response and differ-
ently expressed in young and elderly people (Mocchegiani et al.,
2012a). In particular, genes of pro-inflammatory cytokines (IL-6,
TNF-a), chemokines (CXCL3) are more expressed in zinc deficiency
like in ageing, whereas the peroxisome proliferator activated
receptor (PPAR) signaling (in particular PPARa) is less expressed
(Mazzatti et al., 2007). Taking into account that PPARa inhibits NF-
kB activity, with thus an anti-inflammatory properties (Delerive
et al., 2000), it is evident that a low gene expression of PPARa in
zinc deficiency and in ageing provokes an high degree of
inflammation. Indirect evidences in PPARa knock out mice support
this assumption. In aged PPARa/ mice, zinc supplementation is
ineffective, demonstrating that PPARa is critical in promoting the
anti-inflammatory and anti-oxidative properties (Spencer et al.,
1997). Therefore, zinc plays a peculiar role in affecting the gene
expression of some genes related to the inflammation and
oxidative stress. Sophisticated mechanisms are involved in the
regulation the activity of the complex intracellular zinc–gene
network. In this context, MT are essential regulators for
intracellular zinc homeostasis by the sequestration and release
of the metal at the occurrence and thereby controlling available
free zinc ions and affecting the zinc–gene network. The cysteine
sulfur ligands in the cluster structure of MT can be reduced (zinc
sequestration) or oxidized (zinc release) with concomitant changes
in the relative amount of bound and free zinc (Maret, 2003). MT are
genetically polymorphous protein families with subfamilies,
G Model
MAD-10703; No. of Pages 21
6 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
subgroups and various isoforms, among which MT-I and MT-II
isoforms are the best known and studied (West et al., 1990; Vallee,
1995). One of the main functions of MT-I and MT-II is to regulate
zinc homeostasis and to limit oxidative damage within the cells,
via zinc release from MT by NO and nuclear Nrf2 translocation and
subsequent Gclc gene expression (Spahl et al., 2003). In chronic
stress and inflammation, as it occurs in ageing, high MT are less
able in zinc release with subsequent low zinc ion bioavailability to
fight stress and to support immune responses (Mocchegiani et al.,
2000b). As a consequence, a large number of genes that act as zinc
sensors and transcriptional activators and/or repressors are altered
in ageing (Fulop et al., 2003). In mammalian cells, the metal
responsive transcription factor 1 (MTF-1) was recognized as an
important zinc sensory transcriptional factor. MTF-1 binds to zinc-
sensing gene promoter elements (MRE), and induces the gene
transcription of key target genes, including MT-I and MT-II
(Andrews, 2001). The disruption of MTF-1 gene in mice is lethal
(Andrews, 2001). This finding suggests that MTF-1 gene is
fundamental for MT gene expression and the subsequent regula-
tion of many zinc target inflammatory genes, such as IL-6, TNF-a,
Rantes, IL-8, MCP-1, PPARa, PPARg (Mazzatti et al., 2007). This
finding is of a great interest in ageing and in very old age taking into
account that in centenarians the MT gene expression is low like in
healthy adults and coupled with good zinc ion bioavailability and
satisfactory innate immune response (Mocchegiani et al., 2002).
Therefore, a good zinc–gene interaction, especially MFT-1/MT/
zinc–gene interaction, is preserved in very old age playing a pivotal
role to reach successful ageing and, at the same time, to escape
some age-related diseases. Such an assumption is supported by the
recent discovery of novel polymorphisms of MT2A and MT1A
associated with the inflammatory state, zinc ion bioavailability and
longevity. Old subjects carrying AA genotype for MT2A polymor-
phism display low zinc ion bioavailability, chronic inflammation
and high risk for atherosclerosis and diabetes type II (Giacconi
et al., 2005). By contrast, polymorphism corresponding to A/C
(Asparagin/Threonin) transition at +647 nt position in the MT1A
coding region is the most involved in the longevity (Cipriano et al.,
2006). In addition, +1245 MT1A polymorphism and +647/+1245
MT1A haplotype are implicated in cardiovascular diseases
(Giacconi et al., 2010). These findings are a clear clue of the
relevance of the zinc–MT–gene interaction with a pivotal role in
controlling inflammation and longevity.
An intriguing point is also the finding showing an interaction
among MT polymorphisms, albumin, innate immune response and
cognitive functions in elderly (Mariani et al., 2008b; Marcellini
et al., 2008), taking into account that albumin binds zinc with the
task in moving zinc to various organs and tissues (Cousins, 1986).
Low albumin levels during ageing is associated with sarcopenia
(Visser et al., 2005), kidney damage with the appearance of
nephropathy (Martin and Sheaff, 2007) and mortality with
albumin values of 40 g/L (albuminemia) (Sahyoun et al., 1996).
Polymorphisms of some genes, such as MYO16 (myosin heavy
chain Myr 8), IRS2 (insulin receptor substrate 2), NEGR-1 (neuronal
growth regulator 1), are associated with increased albuminuria
and nephropathy in old mice and humans (Tsaih et al., 2010). Thus,
it is evident the relevance of the zinc–gene interactions in ageing
both in direct form (zinc–MT gene) and indirect form (albumin–
gene) with the subsequent suggestion of possible zinc supplemen-
tation in elderly in order to compensate the lack of zinc. However
caution is needed because zinc may be also toxic with subsequent
undeliverable and deleterious side effects in various systems,
organs and tissues (Prasad, 2012).
3.1.1. Zinc supplementation and zinc toxicity
During these last two decades, a lot of papers report the
beneficial effects of zinc supplementation upon the immune
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
system and the oxidative stress in old mice and in elderly with also
an effect in prolonging the survival in old mice due to a strong
reduction of deaths by infections (Mocchegiani et al., 2008c).
However, contradictory data exist in the beneficial effects of the
zinc supplementation in old people. The discrepancies are largely
due to various factors, among them the different doses of zinc used,
the duration of the zinc supplementation, the dietary habits of the
old subjects with subsequent adverse or toxic effects on the
immune response (Sandstead, 1995) and genomic stability (Sharif
et al., 2012a,b). Zinc supplementation for short periods and in
alternate cycles, as carried out in Down’s syndrome subjects, has
instead beneficial effects upon the immune functions (Franceschi
et al., 1988). However, one possible cause of the discrepancies may
be the choice of old subjects who effectively need zinc
supplementation in close relationship with dietary habits and
inflammatory status (i.e. IL-6 values). This assumption is supported
by the discovery that old subjects carrying GG genotypes (termed
C-carriers) in IL-6 174G/C locus display increased IL-6 produc-
tion, low intracellular zinc ion availability, impaired innate
immune response coupled with enhanced MT. By contrast, old
subjects carrying GC and CC genotypes (termed C+ carriers) in the
same IL-6 174 locus display satisfactory intracellular zinc, good
innate immune response and are more prone to become
centenarians than C- carriers (Mocchegiani et al., 2008a).
Therefore, old C- carriers may benefit more from the zinc
supplementation, which in turn restores NK cell cytotoxicity, zinc
state (Mariani et al., 2008b) and stress response (Mariani et al.,
2008a; Mocchegiani et al., 2007). When the genetic variations of
the IL-6 polymorphism are associated with also the variations of
MT1A +647A/C gene, the plasma zinc deficiency and the altered
innate immune response is more evident (Mocchegiani et al.,
2008a), suggesting that the genetic variations of IL-6 and MT1A are
very useful tools for the identification of old people who effectively
need zinc supplementation. These results suggest that the daily
requirement of zinc might be different in elderly harbouring a
different genetic background with thus the possibility of a
personalized diet. An exhaustive panel showing the effect of the
zinc supplementation on immune and antioxidant parameters in
elderly in relation to IL-6 and MT polymorphisms is reported in
Table 1.
Despite of that, an excess of zinc may become toxic because
inducing copper deficiency (Maret, 2006) perhaps due to a
reduction of the gene expression of ATP7A protein involved in
copper absorption in enterocytes, as it occurs in Menkes disease
(Llanos and Mercer, 2002). Toxic levels of zinc are also implicated
in carcinogenesis because inhibiting the activity of some DNA
repair proteins, such as N-methylpurine–DNA glycosylase and
DNAligase 1 (Yang et al., 1996; Wang et al., 2006). However, an
excess of zinc has the major effect on the brain provoking neuronal
injury with the appearance of neurodegenerative disease (Moc-
chegiani et al., 2005). Toxic accumulation of zinc may result from
either trans-synaptic zinc movement or mobilisation from
intracellular sites, such as Zn flux through receptor associated
calcium channels, voltage-sensitive calcium channels, or zinc-
sensitive membrane transporters (Weiss et al., 2000). Recent
findings have suggested that postsynaptic zinc-sequestering
proteins, such as MT-III, may represent the main sources of toxic
zinc ions (Frederickson et al., 2004) because sequestering and
rapidly releasing zinc after oxidative stimuli (Lee et al., 2003) with
a final role in activating neuronal apoptotic processes (Sensi and
Jeng, 2004). These phenomena occur in Alzheimer type dementia
(AD), in which zinc may also favour the accumulation of b-amyloid
(Ab) in the senile plaques (Bush, 2000). Although this last role of
zinc in Ab accumulation has been instead suggested to be
protective because preventing Ab-copper interaction with the
subsequent formation of hydrogen peroxide and free radicals
G Model
MAD-10703; No. of Pages 21

E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx 7

Table 1
Effect of zinc supplementationa on immune and antioxidant parameters in elderly according to MT and IL-6 polymorphisms (data obtained from Zincage project).

Condition/target Parameter Effects

Stress-related proteins Poly(ADP-ribosyl)ation capacity "

ROS production #
ApoJ plasma –"
Genes involved in Nitrosative stress (ATF2, CSF2, FOS, ICAM1, JUN, LTA, CCL2, SELE, VCAM1, #
iNOS, TNF, NFKB1)
Total intracellular carbonyl levels #
MsR activity and protein expression ""
Chymotrypsin-like peptidase activity of proteasome and 20S protein expression "
Chaperone (Hsp72) protein levels –"
Chaperone (Hsp72) inducibility ""

Antioxidant plasma enzymes Plasma SOD "

Erythrocyte SOD "
Catalase #
Glutathione peroxidase #

Thymic output T-cell receptor excision circles (TRECs) #"

Plasma cytokines and chemokines IL-6, IL-8, MIP-1a –"

MCP-1, RANTES –

Immune functions NK lytic activity ""

Basal IFN-g, IL-8, IL- 1ra and IL-6 production #
Basal IL-10 and TNFa production ##
Stimulated IFN-g, IL-6, TNF-a, IL- 1ra and IL-10 production "

T cells subsets Activated T cells (CD3 + CD25+) #

CD4:CD8 –

"", strongly increased; ", increased; – not modified; –" slightly increased; #", intervariability; #, decreased.
a
The dose = 10 mg/day for 45 days of zinc aspartate (Unizink 50, Kohler Pharma Corp., Alsbach-Hahnlein, Germany; Mocchegiani et al., 2012a, 2013b).

(Cuajungco et al., 2000), an excess of zinc is toxic in the brain with
thus the use of chelating agents in order to avoid the excess of zinc
in AD and neurodegeneration. Among chelating agents, TPEN and
Clioquinol were used. TPEN was used for ‘‘in vitro’’ studies in order
to better understand the zinc release by NO in neurons, via
p38MAPK, and the subsequent its toxic effect on neuronal cell
death (Bossy-Wetzel et al., 2004). Other ‘‘in vitro’’ studies have
shown that TPEN attenuates the upregulation of TNF-a, IL-13, IL-4,
IL-6 by high doses of zinc, via PKC and NF-kB inhibition (Fukuyama
et al., 2011; Haase et al., 2008). The other chelator is Clioquinol that
acts as a zinc, copper, and iron chelator (Cuajungco et al., 2000).
Metal chelation is a potential therapeutic strategy for AD because it
can dissolve amyloid deposits by preventing metal–Ab interac-
tions (Bush, 2000), as shown in transgenic mice with high Ab
peptide levels (Cherny et al., 2001). However, Clioquinol can
potently inhibit the 20S proteasome causing intracellular accu-
mulation of misfolded proteins with thus a deleterious role (Mao
and Schimmer, 2008). This dangerous effect is dependent by the
inflammatory genetic susceptibility and by the dose used. Low
doses of Clioquinol (20–30 mg/kg/day) provoke relatively lower
toxic effects in humans (Bareggi and Cornelli, 2012) (see Table 2).
Anyway also for zinc chelation, the individual inflammatory
genetic background may play a key role in order to visualize
subjects or patients to be treated effectively with zinc chelators. In
such a way, we can establish a nutritional personalized therapy
either in zinc supplementation or zinc chelation.
3.2. Copper and gene interactions
As reported above, copper (Cu) is an essential component for
numerous reactions that are necessary for the growth and
development in men and animals (Olivares and Uauy, 1996).
The most bioavailable source of copper is meat and the major
storage of copper is in the liver primarily bound to MT (Hartmann
et al., 1993). A blood protein, ceruloplasmin (Cp), contains several
molecules of copper and it is a marker of body copper status
because involved, together with albumin, to the transport of
copper within the cells, organs and tissues (Harvey et al., 2009). A
recent adult human dietary recommendation for copper (estimat-
ed safe and adequate dietary intake) was set at between 1.5 and
3.0 mg Cu/day (Milne, 1998). Equipped with high redox potential,
copper serves as a cofactor for proteins involved in a variety of
biological reactions, such as photosynthesis and respiration
(cytochrome c oxidase), free radical eradication (SOD), connective
tissue formation (lysyl oxidase), neurological development (dopa-
mine b-hydroxylase), and iron homeostasis (Cp) (Prohaska and

Table 2
Effect of zinc chelators as potential therapeutic strategy in presence of possible zinc toxicosis.

Chelator Target Model Treatment Effect Reference

TPEN TNFa, IL-13, IL-4 Airway inflammation One i.p. injection (10 mg/Kg) # Fukuyama et al. (2011)
production (animal model)
TPEN TNFa, IL-6, IL-1b Human monocytes after 10–50 mM for 30 min # Haase et al. (2008)
production LPS stimulation for 24 h
(in vitro model)
Clioquinol Ab42 accumulation Alzheimer (human) 375 mg/day for 25 weeks # Ritchie et al. (2003)
EDTA Learning memory HeLa cells exposed to toxic zinc 2 mM " Blocked inhibition of Wang et al. (2006)
N-methylpurine-DNA (50 mM) (in vitro model) MPG by zinc favouring
glycosylase (MPG) DNA-repair

", increase; #, decrease.

Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
G Model
MAD-10703; No. of Pages 21
8 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Gybina, 2004). However, excessive copper is toxic or even lethal
for the cells because participates in ROS generation through
Fenton chemistry and direct oxidations of lipids, proteins and
DNA (Linder and Hazegh-Azam, 1996). Consequently, intracellu-
lar copper content is maintained by evolutionarily conserved cell
transport systems that regulate uptake, export, and intracellular
compartmentalization (Prohaska and Gybina, 2004). Therefore,
in order to prevent the consequences of copper deficiency or
overload, living organisms have evolved molecular mechanisms
that regulate its uptake, intracellular traffic, storage and efflux
(Ridge et al., 2008). High-affinity copper uptake is mediated by
copper transporters Ctr1p and Ctr3p in yeast (Dancis et al., 1994;
Pena et al., 2000) and copper transporter hCTR1 in humans (Puig
and Thiele, 2002). In humans, Cu2+ can be transported directly
into the cells by the divalent metal transporter DMT1 (Arredondo
et al., 2003). Once in the cytoplasm, copper is delivered to various
cell targets with the help of copper chaperones, such as CCS, to
transfer copper to SOD1; COX17 through SCO1/2 to cytochrome C
oxidase and HAH1 (homologous of Atox1) to ATP7A/B located in
the trans-Golgi network. The latter ATP7A/B genes, identified as
P-type ATPases, are very important because their function in the
trans-Golgi network is to pump copper to copper-dependent
enzyme (lysyl oxidase) involved in elastic and collagen cross-
linking and to maintain cellular copper within safe limits (Petris
et al., 1996). Mutations in the ATP7A/B genes are responsible of
Menks or Wilson diseases that are related to copper deficiency or
toxicosis, respectively (Camakaris et al., 1980; Gojová et al.,
2008). When ATP7B is mutated, as in Wilson’s disease, Cp levels
decrease and copper accumulates in the liver, suggesting the key
role played by ATP7B in copper homeostasis (Bull et al., 1993;
Mercer, 2001).
The interaction of ATP7B with specific copper chaperone Atox1
is required in the hepatocytes for proper biliary excretion of excess
copper and for delivery of copper for Cp synthesis (Culotta et al.,
1999). Deletion of the Atox1 gene in mice causes perinatal
mortality (Hamza et al., 2001), provokes reduced levels of lysyl
oxidase (Prohaska and Gybina, 2004) and does not protect the
neurons from oxidative stress (Kelner et al., 2000). Mutants of
Atox1 in the corresponding gene (lys7) are defective for SOD1
activity, and are unable to incorporate copper into SOD1 (Culotta
et al., 1999). With regard to ATP7A, it is an important copper-
transport protein in neurons and astrocytes (Prohaska and Gybina,
2004). When the cells are exposed to increased levels of copper,
ATP7A moves from the trans-Golgi network to the plasma
membrane for copper efflux (Lutsenko and Petris, 2003). In
concert with Atox1, ATP7A also plays a key role in providing copper
for secretory cuproenzymes such as peptidylglycine-amidating
monoxygenase (PAM) (El Meskini et al., 2003). When ATP7A is
non-functional, as in brindled mutant mice, PAM activity is altered,
and the selected neuropeptide maturation is impaired (Steveson
et al., 2003). Moreover, the cells lacking Atox1 have impaired
movement of ATP7A in response to copper, providing a mechanis-
tic explanation for copper retention (Hamza et al., 2003). ATP7A is
also required for the transfer of copper to other cuproenzymes,
such as hephaestin (Prohaska and Gybina, 2004). Therefore, a
copper deficiency in the diet modifies the gene expression and
function of these relevant copper chaperons with the subsequent
altered intracellular copper homeostasis that may also affect the
Cp synthesis. As a consequence, defects in copper distribution and
in iron metabolism may occur because Cp acts also as a ferroxidase,
converting Fe2+ to Fe3+ and increases the rate of loading of Fe into
transferrin (Osaki and Johnson, 1969). Furthermore, Cp stimulates
Fe efflux, suggesting that it is relevant for the mobilisation of Fe
from the body stores (Osaki and Johnson, 1969). Therefore, the
synthesis of Cp by dietary copper is crucial not only for copper body
distribution but also for iron metabolism. Thus, it is evident that
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
dietary copper is fundamental for the copper–iron cross linking in
which the synthesis of Cp plays a key role, as shown by the
presence of four exon polymorphisms of Cp in iron overload
individuals: two of which resulted in an amino acid change, a C3/T
transition in position +1099 (R367C) in exon 6 and a C3/T
transition in position +1652 (T551I) in exon 9 (Lee et al., 2001).
The Cp synthesis and secretion by the liver is regulated by pro-
inflammatory cytokines (IL-1, IL-6, and TNF-a) indicating a role of
Cp in inflammation (Linder and Hazegh-Azam, 1996). Increases of
Cp in inflammation are thought to be related to the need for
scavenging oxygen radicals released at inflammatory sites by the
immune cells (Linder and Hazegh-Azam, 1996). An increase in Cp
levels in ageing, in atherosclerosis or Alzheimer disease (AD), could
represent a good marker of the inflammatory status. On the other
hand, Cp oxidizes LDL through an interaction of one of the copper
molecules carried by Cp (Mukhopadhyay et al., 1997; Fox et al.,
2000), and oxidized LDL is part of the atherogenic and ageing
processes (Windler et al., 2007). With regard to AD, contradictory
data exist on the role played by copper in its pathogenesis. Some
authors report that high copper may be involved in AD because
Amyloid precursor proteins have a copper binding domain which
reduces copper (II) to copper (I) producing oxidative damage
(Multhaup et al., 1996). Moreover, b-Amyloid binds copper and
cholesterol, facilitating copper oxidation of cholesterol to 7–0H
cholesterol, which is extremely toxic for neurons (Nelson and
Alkon, 2005). In animal models of AD, the addition of copper in the
drinking water greatly enhances the accumulation of b-Amyloid in
the brain and increases learning deficits (Sparks, 2004). By
contrast, other authors report that copper induces a reduction of
the b-Amyloid formation (Phinney et al., 2003). All the data,
although some of them are contradictory, suggest in general that
high copper may be deleterious because affecting the gene
expression of copper chaperones, Cp and the copper–iron
interactions with subsequent enhanced inflammation and in-
creased incidence of some inflammatory pathologies, such as
atherosclerosis, AD and type I and II diabetes (Shukla et al., 2006).
Patients with ‘‘metabolic syndrome’’ (obesity, hypertension,
glucose intolerance and dyslipidemia) also have elevated Cp levels
(Kim et al., 2002). With the exclusion of Menkes disease, in which
copper deficiency is of genetic origin (Kaler, 1994), nutritional
copper deficiency is well documented in two situations: (a) the
premature newborn and (b) patients maintained on total
parenteral nutrition for long periods (Danks, 1988). A paucity of
data exists on the effect of copper deficiency in old age. This fact
may be due because copper homeostasis is maintained over a wide
range of intakes, mainly through changes in endogenous excretion,
especially at lower intakes (Harvey et al., 2003). On the other hand,
plasma copper is not different among young, adult and old age with
significant increments in presence of acute inflammation or
inflammatory diseases (Malavolta et al., 2010) mainly due to
increased levels of SOD1 and MT cuproenzymes to fight oxidative
stress and inflammation (Mocchegiani et al., 2006b). Indeed, MT
are another possible copper chaperone, as shown in MT-null
fibroblast cell lines (Tapia et al., 2004). Two MT isoforms, MT-1 and
MT-2, play a role in intracellular copper transfer and storage in the
liver. Indeed, other than zinc, copper can induce MT synthesis
(Coyle et al., 2002). When copper is limiting in liver cells, MT plays
a role by acting as a copper reserve (Suzuki et al., 2002). Therefore,
MT synthesis and production as well as MT polymorphisms
become relevant in presence of inflammation especially in ageing
in order to act as copper reserve also in presence of lower copper
intake. In this context, some novel +647A/C and +1245A/G MT1A
polymorphisms are related to increased copper levels and
enhanced SOD in CVD (Giacconi et al., 2008a), suggesting a role
of MT in the copper transfer to SOD to fight the inflammation and
ROS. However, also a copper deficiency might be relevant in ageing
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
taking into account that a copper deficiency affects some aspects of
the inflammatory/immune response (Mocchegiani et al., 2012a). A
low intake of copper (0.38 mg/day) in adult humans significantly
impairs the ‘‘in vitro’’ responsiveness of T lymphocytes to
mitogenic activation and decreases IL-2 receptor concentrations
(Kelley et al., 1995). In the copper deficient Jurkat T-cell line, the IL-
2 mRNA synthesis was decreased by 50%, indicating that copper
plays an important role in the transcription of the IL-2 gene
(Hopkins and Failla, 1999). Anyway, data showing the effects of
copper on the immune response are limited in elderly, mainly due
to the inability to precisely assess marginal and moderate copper
deficiency state because of the lack of sensitive and specific
biomarkers.
3.2.1. Copper supplementation or copper depletion
The necessity of copper for the human health derives from its
involvement in a myriad of biological processes, including iron
metabolism, antioxidant defense, neuropeptide synthesis and
immune functions (see Section 2.2), but it may be also potentially
toxic when the intake levels are too high (Brewer, 2008) due to its
participation, like iron, in the Fenton-type redox reaction provok-
ing cell oxidative damage (Linder and Hazegh-Azam, 1996).
Therefore, it is important to distinguish two levels of interventions:
the first one as a copper supplementation in the case of copper
deficiency; the second one as a copper depletion in the case of
copper excess. Such a subdivision may seem obvious, but the
matter is not so simple because it is very difficult to find a precise
biomarker for the copper state and, consequently, the deciding for
a copper supplementation or depletion is somewhat problematic.
The difficulty especially arises when the copper state has to be
determined taking into account that neither plasma copper nor
plasma cuproenzymes reflects copper status, which is instead
estimated by intake and exposure assessment. The latter are
subject to the error inherent to all dietary intake studies and, while
suitable for the assessment of macronutrient intake, may not be
precise enough to estimate intake of a dietary micronutrient,
especially for copper due to its content in the drinking water that
can vary in dependence of local changes in the chemical water
properties (water hardness and pH) (Danzeisen et al., 2007). As a
consequence, a large error of dietary copper intake assessment
may occur. Thus, regulators and public health professionals adopt a
predominantly conservative approach in copper-exposure regula-
tion. However, this approach may not be suitable for an essential
trace metal, since a low intake of copper is as dangerous as a too-
high intake. The situation is then worsened by the lack of precise
copper biochemical biomarker/s, despite plasma copper, Cp and
Cu/Zn SOD1 routinely are assayed in human studies (Danzeisen
et al., 2007; Harvey et al., 2009). Therefore, a marginal copper
deficiency is difficult to diagnose with respect to severe copper
deficiency, which is instead present in various pathological
conditions (Danks, 1988), which some of them are also related
to the ageing process, such as macular degeneration, osteoporosis,
myocardial disease (Klevay, 2000). Conversely, copper toxicity as a
result of a dietary excess generally is not considered to be a
widespread health concern, probably as a result of the homeostatic
mechanisms controlling copper absorption and excretion (Turn-
lund et al., 2005). However, a copper overload has been
documented in various pathological conditions usually also related
to the ageing process, such as atherosclerosis, type II diabetes, and
AD, even if in AD the data are strongly controversial reporting also
copper deficiency (Brewer, 2007).
From this complex picture, many studies on the effect of copper
on the immune response, oxidative stress and bone metabolism
and the subsequent copper supplementation or copper depletion
were conducted in animals and in adult humans with low or
excessive copper content in the diet. In order to study the effect of
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
9
copper in ageing, the budding yeast Saccharomyces cerevisiae was
used as a model for cellular ageing (Kirchman and Botta, 2007). The
majority of these studies are conducted testing plasma copper or
cuproenzymes or ceruplasmin for copper state. In copper-deficient
rodents, the reduced secretion and activity of IL-2 by activated
splenocytes is restored by copper treatment (24 mM) (Bala and
Failla, 1992). A similar restoration also occurs for other impaired
immunological functions (burst neutrophil activity, blastogenic
response to T cell mitogens and balance of Th1/Th2 paradigm
(Bonham et al., 2002). Recently, taking into account that copper
deficiency is associated with cardiomyopathy (Klevay, 2000),
copper supplementation can reverse hypertrophic cardiomyopa-
thy in some patients. One example of this is a rare congenital
condition of Sco2 mutations, which affects copper metabolism and
predisposes to hypertrophic cardiomyopathy (Papadopoulou et al.,
1999). Copper supplement (copper–histidine) therapy caused
reversal of the hypertrophic cardiomyopathy along with signifi-
cant improvement in heart functions, normalization of ECG signs
and blood pressure (Freisinger et al., 2004). The mechanism by
which copper induces its beneficial effect is through copper
chaperone for SOD-1 that mediates also VEGF expression and
angiogenesis (Jiang et al., 2007) suggesting a role of copper also in
angiogenesis. This fact is relevant taking into account that reduced
angiogenesis is involved in endothelial cell senescence (Erusa-
limsky and Kurz, 2006) with the appearance of aortic valve
stenosis: a characteristic of the ageing process (Yetkin and
Waltenberger, 2009).
With regard to ageing, few studies exist in animal models and in
humans on the role played by copper. In order to examine the role
played by copper in cellular ageing and the possibility that copper
may reduce oxidative stress in cells, the effect of copper
supplementation on the life span of superoxide dismutase yeast
mutants was assayed. Mutants with a deletion of the SOD1 and
SOD2 genes had extremely short life spans. Copper supplementa-
tion increased the life span of the SOD1 and SOD2 mutants,
indicating that copper supplementation increases longevity by
reducing the production of superoxide (Kirchman and Botta, 2007).
In humans, the copper state, tested by plasma copper or
ceruloplsamin or cuproenzymes, is strictly dependent by individ-
ual dietary habits and healthy state. In particular, both excessive
zinc or iron intake can induce copper deficiency interfering with
copper absorption in enterocytes (Underwood, 1981). However, in
general, the plasma copper does not have any substantial changes
in condition of healthy state during the life of an individual,
including old age, in which a copper deficiency is at subclinical
level (Harvey et al., 2009). By contrast, in condition of specific
intestinal malabsorption (such as celiac disease, bowel syndrome,
in long-term parenteral nutrition), or in bone abnormalities or in
well genetically determined disease (Menkes’ disease) copper
deficiency is severe with dysfunctions related to immune response,
antioxidant activity and bone metabolism (Danks, 1988). In this
last case, copper deficiency is linked to the reduced activity of
enzyme lysyl oxidase with subsequent appearance of osteoporosis
(Lowe et al., 2002). Copper supplementation in old post-
menopausal women induces a better bone mineral density
(Saltman and Strause, 1993) as well as an improved clinical
outcome of elderly patients with femoral neck fracture (Delmi
et al., 1990). Of great interest is the role played by copper
deficiency in the retinal pigment epithelium (RPE) (Ugarte and
Osborne, 2001) provoking apoptosis of RPE and retinal cells as well
as altering the activity of RPE antioxidant metalloenzymes with the
appearance of the age-related macular degeneration (AMD)
(Zarbin, 2004). A reduced zinc pool in RPE may be ascribed to
reduced action of MT (Nicolas et al., 1996), whereas for copper,
reduced copper–adenosine triphosphates (ATPases) has been
proposed taking into account that they are localized in the RPE
G Model
MAD-10703; No. of Pages 21

10 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx

Table 3
A,B. Effects of copper supplementation and copper chelation in copper deficiency and in copper overload, respectively.

Condition Type of supplementation Target Effect

A. Effect of copper supplementation in copper deficiency

Neutropenia (animal model) (Bala and Failla, 1992) 6 mg of Cu in the diet for 5 weeks Macrophage functions "
Neutrophils activity "
IL-2 mRNA "
NK cytotoxic activity "
Th1/Th2 balance Normalization
T-cell proliferation "
ECG Normalization

Menkes’ disease (human) (Kreuder et al., 1993) S.c. injections of Cu-histidine IL-2 "
(65 mg/kg/day/120 days) NK cytotoxic activity "
SOD "

Macular degeneration (human) (AREDS Study, 2001) 80 mg zinc oxide + 2 mg of cupric Apoptosis of retinal pigment epithelium #
oxide/day for 4–11 years Metallothionein "
Osteogenesis in postmenopausal women (human) 3 mg CuSO4/day for 2 months Bone mineral density "
(Saltman and Strause, 1993)

Alzheimer (animal model) (Bayer et al., 2003) 25 g/L of CuSO4 in H2O for 3 months SOD "
Ab accumulation #
B. Effect of copper chelation in copper overload
Condition Type of Chelator Target Effect

Type II diabetes (human) (Cooper et al., 2004) Trientine (1.2 g/day/6 months) Left ventricular hypertrophy (LVH) Normalization
Wilson’s disease (human) (Brewer et al., 2009) Tetrathiomolybdate (120 mg/day/8weeks) Ceruloplasmin and copper levels #

Alzheimer (human) (Squitti et al., 2002) Penicillamine (600 mg/day for 24 weeks) SOD "
Ab accumulation #
Cognitive status "

Alzheimer (animal model) (Cherny et al., 2001) Clioquinol (oral treatment of Ab accumulation #
30 mg/kg/day for 9 weeks) Survival "

", increase; #, decrease.

and facilitate copper transport between RPE and retina (Krajacic
et al., 2006). Combined oral supplementation of copper plus zinc
reduces the risk of progression of AMD in old patients due to better
MT homeostasis and increased SOD (Erie et al., 2009) (Table 3A).
With regard to high copper, the presence of chronic inflamma-
tion plays a pivotal role taking into account that pro-inflammatory
cytokines affects the synthesis and production of Cp (Linder and
Hazegh-Azam, 1996), which in turn is under the control of copper
status, with thus a strict interrelationship among inflammation, Cp
and copper plasma levels. Such a link is evident in some
inflammatory pathologies, such as atherosclerosis and type II
diabetes, which are also common age-related diseases. Epidemio-
logic studies have shown a relationship between high serum
copper or elevated Cp levels and atherosclerosis (Ford, 2000;
Klipstein-Grobusch et al., 1999), whereas other epidemiologic
studies failed (Enbergs et al., 1998). On the other hand, elevated
levels of copper have been found in human atherosclerotic plaques
oxidizing LDL (Stadler et al., 2004), which is in turn a part of the
atherogenic process, especially in the early phase of the
atherogenesis (Ferns et al., 1997). Elevated levels of Cp and copper
have been found in diabetes mellitus with vascular complications
(Shukla et al., 2006). All these studies show, on one side, that high
copper is toxic because generating ROS; on the other side, they
suggest that a clinical trial of copper depletion may be of benefit in
atherosclerosis. However, no clinical trial of copper depletion in
atherosclerosis or diabetes mellitus have been carried out up to
date. Promising data are obtained in diabetic animal models using
copper chelator trientine (Cooper et al., 2004) with beneficial
effects on the cardiomyocyte structure. Other studies in mouse
model of Wilson disease, the copper-lowering agent tetrathiomo-
lybdate (TM) is capable of producing a greater degree of copper
depletion than other drugs (Brewer, 2007) (Table 3B).
Of particular interest is the role played by copper in AD with
contradictory data and suggestions (Quinn et al., 2009). In this
context, Squitti et al. (2002) have found high free copper coupled
with high levels of serum peroxides in the blood of AD patients.
Penicillamine (a copper chelator) therapy reduced the level of the
serum peroxides (Squitti et al., 2002) (Table 3B). In animal studies,
Sparks (2004) has found that trace amounts of copper added to the
drinking water in a rabbit model of AD greatly enhances the e3/3
accumulation of b-Amyloid in the brain and increased learning
deficits. The treatment with clioquinol markedly inhibited b-
Amyloid deposition in the brain (Cherny et al., 2001). However,
there is significant controversy over whether an excess of copper is
involved in AD pathogenesis, taking into account that copper
supplementation in AD mouse model (APP23 transgenic mice)
lowered b-Amyloid production, restored SOD, and increased the
longevity (Bayer et al., 2003). By contrast, human AD studies show
that the cognitive decline correlated positively with low plasma
levels of copper (Pajonk et al., 2005) suggesting a possible copper
supplementation. Such a controversy can to be resolved by further
experimentations. Anyway, a significant help to discern this
problem in AD may come by the analysis of Apolipoprotein-E4
(ApoE4) genotype that is a risk factor for AD involved in copper
binding of the cysteine residue provoking a diminished antioxidant
effect of the E-4 allele (Miyata and Smith, 1996). In AD, the
presence of ApoE-e4 allele is associated with increased brain
vulnerability to the effects of the disease, whereas the presence of
the ApoE genotype e3/e3 appears to provide moderate neuropro-
tection (Alberts et al., 1995). This finding is very suggestive because
the possible association between these genotypes and copper state
may be very useful to discern the role played by copper in AD with
subsequent possible copper supplementation or deletion.
3.3. Selenium gene–interactions
Selenium is an essential dietary factor for the prevention of
some diseases, including cancer and infections (Schwarz, 1976).

Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
G Model
MAD-10703; No. of Pages 21

E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx 11

Table 4
Main encoded proteins affected by selenium–gene interactions.

Encoded Proteins Gene name Functions Target organs

Glutathione peroxidase 1 Gpx1 Reduction of hydrogen peroxide Mitochondria

Glutathione peroxidase 2 Gpx2 Antioxidant defence Liver, intestinal tract
Detoxification
Glutathione peroxidase 3 Gpx3 Reduction of hydrogen peroxide Skeletal muscle, kidney, lung, breast
Glutathione peroxidase 4 Gpx4 Protection against lipid hydroperoxides Cell membrane
Selenoprotein W Sepw1 Redox reaction Skeletal muscle, heart, brain
Selenoprotein H SelH Cell viability Neuronal cells
Antioxidant defence
Detoxification
Selenoprotein 15 Sep15 Protection from protein folding Endoplasmic reticulum
Selenoprotein P Sepp1 Selenium transport Neurons
Protection against inflammation
Selenoprotein X1 Sepx1 Incorporation in MSRB1 Liver, kidney
Protection from oxidative stress
Selenoprotein I SelI Protection against lipid hydroperoxides Cell membrane
Selenoprotein T SelT Redox regulation Neuroendocrine secretion (pituitary)
Cell adhesion
Cell anchorage
Selenoprotein S SelS Protection against ROS Cell membrane
Selenoprotein K SelK Regulation Ca2+ flux against infections Immune cells
Selenoprotein M SelM Protection on ROS mediated-apoptosis Brain (hippocampus)
Selenoprotein O SelO Defence against toxic substances and ROS Liver
Thioredoxin reductase 1 Txnrd1 Antioxidant and redox regulation Against cancer cells (target for cancer therapy)
Thioredoxin reductase 2 Txnrd2 Redox regulation of cell signaling Prostate, ovary, liver, testis, colon, small intestine, brain, heart
Thioredoxin reductase 3 Txnrd3 Defence against oxidative stress Mitochondria

For specific references see the text (Section 3.3) and Brigelius-Flohe and Banning (2006).

Some relevant papers report a greater development of carcinoma
by various carcinogens (1,2-dimethylhydrazine or dimethylben-
z(a)anthracene) in various organs (colon and mammary gland) in
rats fed a selenium deficient diet in comparison with rats treated
with 5 ppm of selenium (Pence and Buddingh, 1985). With regard
to infection, decreased dietary selenium can change a normally
avirulent B3 coxsackievirus (CBV3/0) into a virulent virus (CBV3/
20) by inducing changes in viral RNA polymerase mutations (Beck
et al., 1994) provoking dilated cardiomyopathy and death (Funseth
et al., 2000). In food, selenium derives from the consumption of
seafood, liver, and cereals. In vegetables and cereals the amount of
selenium varies depending on the soil where they are grown and
harvested from different geographical regions. Indeed, selenium
deficiency and some related diseases have been well documented
in geographic regions where the selenium content on the soil is
low, such as the Chinese province of Keshan, from which derives
the term ‘Keshan disease’ characterized by selenium deficiency
and presence of substantial number of virulent viruses, including
coxsackieviruses (Li et al., 2013).
Mammals can use both inorganic and organic selenium as a
nutrient. Most of the biological functions of selenium are
attributed to selenoproteins, which contain selenocysteine (SeCys)
residues responsible for their specific activity. The human
selenoproteome consists of 25 selenoproteins, mostly involved
in antioxidant defence systems and affecting various target organs
(Brigelius-Flohe and Banning, 2006) (Table 4). The incorporation of
SeCys into selenoproteins occurs during translation by a mecha-
nism that uses UGA codon and the formation of a complex
involving a RNA stem-loop structure, the Selenocysteine Insertion
Sequence (SECIS), which is located in the 30 untranslated region
(30 UTR) of selenoprotein mRNASs (Hatfield and Gladyshev, 2002).
Thus, single nucleotide polymorphisms (SNPs) in selenoprotein
gene regions corresponding to 30 UTR sequence could affect the
expression of the selenoproteins with subsequent influence on the
antioxidant systems or the inflammatory/immune response
(Bermano et al., 2007). In this context, a variety of studies report
the role played by a family of the selenoproteins named Glutatione
peroxidises (GPxs), which protect the cells against oxidative
damage by catalysing the reduction of the hydrogen peroxide and
other hydroperoxides by glutathione (Hayes and McLellan, 1999).
It has been reported that a SNP within the coding region of the gene
encoding the selenoprotein glutathione peroxidase 1 leads to an
amino acid change (Pro to Leu) that leads to a lower enzymatic
activity (Forsberg et al., 2000) with subsequent disease suscepti-
bility, in particular to the lung, breast and bladder cancer.
However, such a susceptibility is still more evident when this
SNP is associated with another SNP in the gene encoding the
antioxidant defense protein manganese dismutase or with
environmental factors, such as alcohol consumption or smoking
(Raaschou-Nielsen et al., 2007). Several studies have also reported
a Pro-to-Leu change in the 30 UTR region of other isoforms of GPxs,
such as GPx2, GPx3, GPx4. While no data report a functional
significance of a SNP for GPx2 gene, a recent study has instead
indentified up to eight strongly linked variants in the promoter
region of GPx3 gene that fell into two haplotype groups indicating
a lower activity of the enzyme with the possible appearance of the
arterial ischemic stroke in adults (Voetsch et al., 2007). Taking into
account that GPx4 removes membrane-bound phospholipid
hydroperoxides inhibiting lipoxygenases and affects the leukotri-
ene biosynthesis, cell growth, apoptosis and inflammation (Kim
and Milner, 2001), a SPN for GPx4 gene was extensively studied in
relation to diseases and selenium metabolism. In this context, a T/C
SNP located within the GPx4 region corresponding to the 30 UTR
near the SECIS element in position 718 show that the C variant is
related to a higher frequency to colorectal cancer, suggesting a link
between this SNP and cancer (Bermano et al., 2007). Of interest is
the recent discovery showing more responsiveness to GPx4
activity in CC subjects than TT ones after selenium supplementa-
tion, suggesting that a SNP in the GPx4 gene a T/C variation at
position 718 close to SECIS, has also functional consequences
(Meplan et al., 2008). The same paper (Meplan et al., 2008) also
reports a hierarchy on the effect of selenium supplementation on
GPxs expressed in the same 30 UTR coding region, in particular
GPx1 e GPx3, showing that CC subjects are also more responsive-
ness than TT ones to increase both GPx1 and GPx3 activity. Such a
finding is relevant because indicating the potential importance of
the SNP in the GPx4 gene especially when selenium intake is
suboptimal with subsequent defects also in GPx1 and GPx3 gene

Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
G Model
MAD-10703; No. of Pages 21
12 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
expression and activity. Data from GPX-KO mice confirm the
relevance of glutathione peroxidases. From experiments in GPx1-
KO mice, the absence of GPx-1 causes the loss of protection of mice
from viral-induced myocardititis in comparison to wild-type mice
(Beck et al., 1998), suggesting that GPx-1 provides protection
against viral-induced damage.
Of particular interest is the gene encoding the plasma
selenoprotein P (SEPP) since this protein has a crucial role in
selenium transport and delivery of hepatic selenium to other
tissues (Schomburg et al., 2003). SePP is unique in containing
multiple selecysteine per molecule (up to 10 in the human SePP)
and it has two SECIS in its RNA (Hesketh, 2008). The central role of
SePP in the selenium transport makes likely that variants in the
SePP gene could have significant functional consequences. In
particular, two SNPs in the SePP gene, one in the coding region 234
in position 24731 (SNP Ala234Thr) causing Ala to Thr change, and
the other one in the 30 UTR region in position 25191 (r25191) are
known (Meplan et al., 2007). In both SNPs, G-to-A variations are
present. The frequencies of the allele variations in position 24731
and 25191 are different in dependence of the ethnicity (Caucasian
vs Chinese groups) (Meplan et al., 2007). This fact is relevant
because it illustrates the importance of considering ethnicity in the
studies of nutrient–gene interactions. Such a different frequency is
also evident after Se supplementation (SELGEN study) (Meplan
et al., 2007), in which subjects with different SNPs within the same
SePP gene display, in a gender-specific manner, different baseline
SePP levels, differences in GPx3 activity as well as in erythrocyte
thioredoxin reductase 1 concentrations and lymphocyte glutathi-
one peroxidase 1 and 4 activities. These findings demonstrate that
a number of SNPs in selenoprotein genes may have functional
differences between the allelic variants. Therefore, when assessing
the impact of the variants on selenium metabolism, it is important
to consider the known hierarchy and competition among
selenoproteins because changes in the synthesis of one seleno-
protein may alter another selenoprotein (Hesketh, 2008; Hesketh
and Meplan, 2011). Therefore, the genetic variations of one SNP
may be magnified or counterbalanced by variants in other genes
with subsequent different modulation on selenium metabolism.
For example, an SNP in the SBP2 gene might affect selenium
incorporation but without consequences unless combined with an
SNP in the 30 UTR of the GPx4 gene (Hesketh, 2008). The effect of the
SNP in GPx1 might be magnified by an SNP in SePP gene that affect
the selenium delivery to target tissues (Hesketh, 2008). Another
example is the presence of two SNPs in the region of Sep 15 gene
that correspond to the 30 UTR of the mRNA (Hu et al., 2001). The
combination of these two variants, a C/T substitution at position
Table 5
Associations of selenoprotein polymorphisms with cancer and cardiovascular diseases.
Polymorphism Disease
GPx4T/C 718 genotype Colorectal cancer
SEPP1 4166C/G Colorectal adenoma
SEPP1 loci (31,174 bp 30 of STP A/G Colorectal adenoma
SEPP1 43,881 bp 30 of STP G/A Colorectal adenoma
SEPP1 44,321 bp 30 of STP C/T Colorectal adenoma
TXNRD1 IVS1-181 Colorectal adenoma
Gpx1 Leu 198 Pro Bladder cancer risk
Lung cancer risk
Breast cancer
Cardiovascular disease (CAD)
SEPS1 (rs8025174) A/C Coronary heart disease (CHD)
SEPS1 (rs7178239) C/G Stroke
SEPS1 105G/A Gastric cancer
Sep15 1125 G/A Lung cancer
SEPP1-Ala234Thr Prostate cancer
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
811 and a G/A at position 1125 influences read-through at a UGA
codon (Hu et al., 2001). Here, the significant differences in Sep15
allele frequencies is affected by ethnicity and the identity of the
nucleotides at the polymorphic sites influences SECIS function in a
selenium-dependent manner, suggesting that the loss of hetero-
zygosity at the Sep15 locus may be involved in cancer develop-
ment. More recently, two genetic variants of SePP1 gene at position
31174 and 43881 when associated to genetic variants of another
selenoprotein thioredoxin reductase 1 (TXNRD1) at position 181
were strong predictors for advanced colorectal adenoma and
subsequent selenium dismetabolism (Peters et al., 2008).
Up to date, the research on nutrient–gene interactions in
relation to selenium metabolism is quite limited to studies to
individual SNP in relation to measurements of physiological
parameters. A G/A SNP at position 105 in the promoter of
Selenoprotein S appears as functionally significant. It modulates
the response to stressors and affects the markers of inflammation,
such as TNF-a and IL-1b (Curran et al., 2005). The promoter region
of SePP1 gene is also cytokine responsive, suggesting a role of
SePP1 on the inflammation (Dreher et al., 1997). Several other
lines of work indicate various polymorphisms of selenoproteins,
such as GPx1 and GPx4, with a functional significance, in
particular in response to inflammation and oxidative stress
(Seiler et al., 2008). Considering the selenium intake and the
genetic factors, the picture that is emerging is a complex one of
multiple, possibly interacting, functional SNPs, the influence of
which may be modulated by the ethnicity, gender, life style and
dietary factors. Therefore, no data report the role played by SNPs
of selenoproteins in ageing up to date. By contrast, a substantial
number of papers report the effect of some SNPs of the
selenoproteins in age-related diseases (cancer and CVD). On this
topic, an exhaustive review of Ryan-Harshman and Aldoori (2005)
reports all the selenoproteins involved in cancer and CVD, in
which GPx1 and SepS1 are the more relevant SNPs for the risk of
cancer and CVD. The Gpx1 Leu 198 allele confers an increased risk
of bladder cancer. In particular, subjects carrying the Pro/Leu
genotype with respect to Pro/Pro genotype have a higher risk
(Ichimura et al., 2004), as also reported for lung cancer by a Finnish
study (Ratnasinghe et al., 2000). Another study reports a higher
Leu/Leu genotype frequency in breast cancer than Pro/Pro
genotype, while a lower heterozygosity index has been observed
in the breast cancer samples suggesting an allelic loss during the
tumor development. By contrast, A Danish study reports an
association with decreased risk for lung cancer in subjects
carrying Leu/Leu genotype with respect to Pro/Leu genotype
(Raaschou-Nielsen et al., 2007) (Table 5).
Findings Ref.
CC genotype increased cancer risk Bermano et al. (2007)
CG genotype increased cancer risk Peters et al. (2008)
GG genotype increased adenoma risk Peters et al. (2008)
AA genotype increased adenoma risk Peters et al. (2008)
CT genotype reduced adenoma risk Peters et al. (2008)
CG + GG genotypes decreased cancer risk Peters et al. (2008)
Pro/Leu genotype increased bladder cancer risk Ichimura et al. (2004)
Pro/Leu genotype increased lung cancer risk Ratnasinghe et al. (2000)
Leu/Leu genotype increased breast cancer risk Hu and Diamond (2003)
Pro/Pro genotype increased CAD risk Tang et al. (2008)
A allele increased CHD risk in females Alanne et al. (2007)
G allele increased stroke risk in females Alanne et al. (2007)
A allele increased cancer risk in males Shibata et al. (2009)
GG or GA genotype increased lung cancer risk Jablonska et al. (2008)
in patients with low Se status
Ala/Ala genotype associated with SOD2-Ala16+ Cooper et al. (2008)
genotype increased prostate cancer risk
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
With regard to CVD, subjects with 198Pro/leu and 198Leu/leu
genotypes had a significantly higher risk of CVD compared to the
198Pro/Pro carriers, suggesting that GPX1 198Pro/Leu variant
genotypes are significantly associated with CVD risk (Tang et al.,
2008) and with thoracic aortic aneurysm in hypertensive patients
(Kato et al., 2008). The selenoprotein SEPS1 is also of particular
interest for CVD because is able to mediate the inflammation
through the protection of the endoplasmic reticulum (ER) (Ross,
1999).
SEPS1 is an ER membrane protein that participates in the
processing and removal of misfolded proteins from the ER to the
cytosol, via NF-kB activation, which in turn activates the
transcription of the pro-inflammatory genes (Curran et al.,
2005) and SEPS1 (Gao et al., 2006). Increased expression of SEPS1
suppresses the cytokine production by its ability to remove
misfolded proteins from the ER. This system constitutes a SEPS1-
dependent regulatory loop in the presence of inflammation
(Curran et al., 2005). Variation in the SEPS1 gene affects the
circulating levels of the inflammatory cytokines IL-1b, IL-6 and
TNF-a (Curran et al., 2005). Given the known association of SEPS1
with the inflammation, the effect of the genetic polymorphisms in
SEPS1 on the risk of CVD was investigated in two independent
Finnish cohorts. A significant association was found with an
increased risk for coronary heart disease (CHD) in females carrying
the minor allele of rs8025174. Another variant, rs7178239,
increased the risk for the ischemic stroke in females (Alanne
et al., 2007). These results implicate that the selenoprotein SEPS1 is
involved in the risk of CVD in female. With regard to cancer, taking
into account that the 105G > A polymorphism in the promoter of
SEPS1 increased the pro-inflammatory cytokines (Gao et al., 2006),
SEPS1 is a key factor in the process of carcinogenesis from chronic
gastritis induced by Helicobacter pylori (El-Omar et al., 2001). The
105G > A promoter polymorphism of SEPS1 was associated with
the type of gastric cancer. In particular, old subjects (>65 years)
carrying the A allele display an increased risk of both gastric cancer
and inflammatory state when compared with the GG genotype
(Shibata et al., 2009). Also other SNPs for selenoproteins, such as
Sep 15 and SEPP1, are involved in cancer risk. A case–control study
in a population of Polish smokers with low selenium state
(53.3  14.0 mg/L), showed an effect of Sep15 G/A1125 genotype
on lung cancer risk. Among individuals of lower selenium state
(below 50 mg/L), the risk was higher in individuals with AA genotype
as compared to those ones with GG genotype, suggesting that the
subjects carrying AA genotype might have a benefit by increasing
dietary in selenium (Jablonska et al., 2008). Recently, it has been also
reported that homozygous for SEPP1 ala234 SNP allele in men had a
high risk for prostate cancer with a more aggressive form when this
SNP was associated with SOD2-Ala16+ allele (Cooper et al., 2008)
(Table 5)
Form all these data, it emerges a complex picture on the effect of
selenoproteins and of their relative SNPs on the health especially
because few intervention studies have been carried out to assess
the functionality of SNPs in vivo up to date. There is the need to
assess SNPs in human intervention studies using genotyped
cohorts and appropriate biomarkers in order to show the
relationship between selenium, SNPs and the biomarkers of the
healthy state. Trascriptomic approaches, as reported above, have
provided interesting data on the response of the selenoprotein
genes and on the role played by some SNPs for selenoproteins in
some degenerative diseases, but in general the data are limited by
the major regulation of selenoprotein synthesis at the level of
translation. Proteomic methods, in combination with inductively
coupled plasma spectroscopy to detect selenoprotein profiles and
species, need to be developed.
However, taking into account that the selenoproteins are
mainly involved in the protection against oxidative damage and
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
13
inflammation (Ryan-Harshman and Aldoori, 2005), many studies
report the role played by selenium deficiency and selenium
supplementation in ageing and in age-related disease without
considering the SNPs of the selenoproteins, but exclusively based
on the selenium content in the plasma. Although this fact is a limit
on the effect of selenium supplementation on functional param-
eters related to the stress and inflammation, it does not exclude
that these studies of the selenium supplementation may be
relevant to better understand the role played by selenium in
maintaining the healthy state.
3.3.1. Selenium supplementation in Ageing
Selenium deficiency is a condition mainly attributed to low
selenium content in the soil or to long-term parenteral nutrition.
During ageing, selenium deficiency may occur as a result of
intestinal malabsorption. However, few data are available
reporting a marked selenium deficiency in old subjects (Seiler,
2001). Recently, a paper has explored the relationships between
plasma selenium and mortality in an elderly population for a long
period of observation (9 years): the EVA study (Arnaud et al.,
2007). The authors have observed that the mortality rates were
significantly higher in individuals with low selenium [1.01 mmol/
L: a value below the cut-off considered as optimal (1.25–
1.50 mmol/L)] (Arnaud et al., 2007). Considering the causes of
death, an association was found with low selenium and cancer-
related mortality. The same authors suggest that plasma selenium
could be an indicator of the longevity in a middle-aged,
independently living population not specifically at risk for cancer
and CVD. The survival curves illustrate that the relationship
between plasma selenium and mortality remained constant
during the entire 9-year period of follow up (Akbaraly et al.,
2005). However, the mechanism of this potential relationship is
still under debate and further research is needed on the role
played by selenoproteins, especially at genetic level, on this
phenomenon. Some other authors demonstrate the selenium
deficiency in elderly people in relation to hypothyroidism
(Olivieri et al., 1996). Interestingly, human healthy centenarians
display selenium values quite similar to the normal elderly
(Savarino et al., 2001). Since few trials have been carried out up to
date in elderly, it is difficult to report a specific beneficial effect of
selenium in human ageing, even if the beneficial effects of the
selenium supplementation on lymphocyte mitogen responsive-
ness have been reported in institutionalized old individuals
(Peretz et al., 1991). Moreover in a Finnish study, the addition of
selenium to fertilizer leads to an improved selenium state in the
general population (young–adult, old) (Aro et al., 1995). However,
the possible beneficial on the health was not reported in this study
(Table 6A).
The major evidences on the beneficial effects of selenium
supplementation relate to age-associated diseases, such as cancer,
cardiovascular diseases (CVD), diabetes and infections. On this
topic, various papers report the beneficial effect of selenium
supplementation, but the beneficial effect of selenium ‘‘in se’’ are
not conclusive. Different studies [SUVIMAX study (Reid et al.,
2006); SELECT study (Lippman et al., 2009)] have reported an effect
in preventing cancer in adult and old people with also contradic-
tory results. No specific effect of selenium supplementation was
observed both in diabetes (Faure et al., 2004; Bleys et al., 2007;
Stranges et al., 2007; Yang et al., 2010) and CVD (Czernichow et al.,
2005; Nawrot et al., 2007). An intriguing point is the association
between selenium deficiency, immune response and increased
incidence of viral infections in elderly (Ellis et al., 2003), suggesting
that the selenium deficiency may be considered a relevant risk
factor for the appearance of infections by viruses. Such an
assumption is supported by experiments in animals, in which a
normally-benign strain of coxsackievirus B3 becomes virulent
G Model
MAD-10703; No. of Pages 21
14 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Table 6
Selenium supplementation in ageing (A), age-related diseases (B) and selenium toxicosis (C).
Dose Effect
A. Effect of selenium supplementation in ageing
100 mg/day Improved response of lymphocytes to mitogens
6 mg kg-1 in soil Improved selenium state
B. Effect of selenium supplementation in age-related diseases
200 mg/day Cancer prevention
50 mg/day Cancer prevention
100 mg/day + other nutrients Cancer prevention
200 mg/day + vitamin E No prevention of prostate cancer
100 mg/day + other nutrients No effect on risk of hypertension
960 mg/day NF-kappaB activity reduction and GPx activity
increase in erytrocytes from type 2 diabetic patients
200 mg/day No prevention of type 2 diabetes risk
C. Selenium toxicosis
1 mg/day Thickened, fragile, honeycomb-like fingernails
5 mg/day Nail deformation, hair loss, skin lesion tooth decay,
neurological disorders
when inoculated in selenium-deficient animals due to viral
genomic changes (Beck, 1999) (Table 6B).
With regard to selenium toxicosis, it is a rare event in humans
and very limited specific data exist in literature (Table 6C) The
toxicity of selenium, in the form of Selenium–methyl-selenocys-
teine, mainly occurs in animals eating plants containing from 100
to 10.000 ppm of selenium provoking a subacute selenosis called
‘‘blind staggers’’, characterized by anorexia, emaciation, alopecia,
hoof necrosis, neurologic deterioration-blindness, ataxia, disorien-
tation and respiratory distress and finally also death (Combs and
Combs, 1986).
In conclusion, selenium is a relevant trace element for many
body homeostatic mechanisms but is it important to assess how
the individual genetic background for selenoproteins may affect
the interaction of SNPs with each other or with selenium intake,
ethnicity and gender. In such a way, a more complete picture on
the effect of selenium after supplementation or in the diet may be
given with subsequent beneficial effects on the healthy state in
ageing.
4. Conclusion and future perspectives
Despite the pivotal role played by zinc, copper and selenium for
the inflammatory/immune response and antioxidant activity in
ageing and in some age-related diseases, controversial findings
exist on the ‘‘real’’ necessity of micronutrient supplementation in
deficiency or micronutrient chelation in toxicosis. The contradic-
tory results are mainly due to a great interindividual genetic
variability, to the interaction between environmental (dietary
habits) and genetic factors and to the unreliability of specific
biomarkers for testing zinc, copper and, selenium status in the
plasma. Moreover, the discrepancies may be more due to the fact
that these micronutrients affect many genes related to the
inflammation and oxidative stress, which in turn affect the
intestinal absorption of the micronutrients. Alterations in the
absorption or dietary intake of zinc, copper and selenium may lead
to an incorrect inflammatory/immune response, impaired antiox-
idant activity and unsatisfactory DNA repair to various external
noxae with the subsequent appearance of some age-related
degenerative diseases. Differently, a correct diet as well as
adequate polymorphisms are useful to reach healthy ageing and
longevity (Fig. 1). On the other hand, the relevance of the cytokine
production in maintaining a correct Th1/Th2 paradigm, with
subsequent satisfactory inflammatory/immune response, has been
well documented in ageing in relation to the three micronutrients
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
Period References
6 months Peretz et al., 1991
6 years Aro et al., 1995
7 years Reid et al. (2002)
5 years Blot et al. (1995)
8 years SU.VI.MAX trial. Meyer et al. (2005)
7–12 years SELECT study. Lippman et al. (2009)
5–6 years SU.VI.MAX trial. Czernichow et al. (2005)
3 months Faure et al. (2004)
7.7 years Stranges et al. (2007)
2 years Fan and Kizer (1990)
10 years
herein reported. Taking into account that pro-inflammatory
cytokines also affect the absorption and the distribution of zinc,
copper and selenium within the body (Prasad, 2000), a vicious
circle arises with deleterious or limited beneficial effects of the
micronutrients themselves on inflammatory/immune response
and antioxidant activity (Mocchegiani et al., 2012a). In this
context, polymorphisms of pro-inflammatory cytokines and MT
are very useful tools to screen old subjects who effectively need
micronutrient supplementations with subsequent beneficial effect
upon the inflammatory/immune response and antioxidant activity
(Fig. 1). Indeed, subjects can be screened for zinc supplementation/
chelation on the basis of IL-6 and MT polymorphisms and for
copper supplementation/chelation on the basis of SOD1 and SOD2
polymorphisms regardless to the nutritional state and inflamma-
tory condition. Such a genetic screening is very useful both in
ageing and in age-related diseases taking into account the
existence of a strictly relationship between copper and zinc and
by the recent discovery showing Cu/Zn ratio as a predictor of
disability and mortality in ageing (Malavolta et al., 2010;
Mocchegiani et al., 2012b). With regard to selenium, specific
selenoprotein polymorphisms, such as SEP-15, SEPP1, SEPS1, can
be very useful to screen subjects to prevent cancer. However,
selenium is important in conferring activity to GPx, which is
fundamental for the zinc release from MT via glutathione oxidation
(Khatai et al., 2004), suggesting also the existence of a close link
between zinc and selenium bioavailability. Such a link is pivotal for
the antioxidant activity of many zinc-dependent enzymes and for
the activity of the nuclear enzyme PARP-1. During ageing, PARP-1-
mediated poly(ADP-ribosyl)ation and GPx decrease. The decreased
PARP-1 activity might be in part the result of a low zinc ion
bioavailability due to a limited zinc release by the S-glutathionyla-
tion of MT (Casadei et al., 2008). As a consequence, PARP-1 activity
is altered and may fail in the activation of DNA-repair mechanisms
causing cell death. Therefore, the combination of polymorphisms
of MT and selenoprotenis cited above may be useful tools to
effectively screen old subjects for a correct selenium supplemen-
tation in order to prevent some degenerative diseases, including
cancer. However, such a screening may not be sufficient because it
is necessary also to evaluate the zinc, selenium and copper status
of old individuals. In this context, hyphenated techniques based on
coupling chromatographic separation techniques, mainly HPLC,
with ICP-MS detection are now established as the most realistic
and potent analytical tools available for the speciation analysis of
the essential trace elements (Sanz-Medel and Montes-Bayon,
2003). This novel technology has been recently developed in our
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Fig. 1. Schematic representation of the possible beneficial interactions between dietary micronutrients (Cu, Se, Zn) intake and the related genes in inducing a satisfactory
cellular homeostasis, genomic stability and DNA repair in ageing. The inflammatory status (inflammaging) determined by an inbalance among anti-inflammatory, pro-
inflammatory cytokines and chemokines plays a key role affecting both genomic stability and the absorption/transport of micronutrients. A correct balance of the
interrelationship micronutrient-gene-inflammation leads to healthy status and longevity.
INRCA laboratory and it is very useful to test precisely the quota of
the trace element bound to its specific protein, such as albumin for
zinc, Cp for copper, selenoprotein-P for selenium with an error of
less 10% (Malavolta et al., 2012). Such determinations were useful
at clinical level to better characterize some pathologies (El Balkhi
et al., 2010; Vinceti et al., 2013).
In conclusion, the study of nutrigenetic and nutrigenomic
approaches can be therefore pivotal for the best use of nutrients as
supplements or chelators in clinical practice during ageing and in
age-related diseases. However, further genetic-nutritional studies
are required to clearly define the impact of these micro-nutrients
in promoting healthy ageing and longevity. Surely, the micronu-
trient–gene interactions and the metal speciation analysis are
fundamental for personalized nutritional interventions aimed at
preventing many age-related inflammatory degenerative diseases,
such as cancer, CVD and type II diabetes.
Conflict of interest
No conflict of interest by the authors, who have agreed to
submit and to eventually publish the manuscript in Mechanisms of
Ageing and Development.
Acknowledgments
Supported by INRCA; European Zincage project (FP6 n. FOOD-
2004-506850); European Markage project (FP7 n. HEALTH-F4-
2008-200880); Italian Health Ministry (R.F. 154/GR n. 2009-
1584108 ‘‘My Mind’’). We thank Dr. Aurelia Santoro, Scientific
Manager of NU-age project, for useful suggestions and criticisms.
References
Akbaraly, N.T., Arnaud, J., Hininger-Favier, I., Gourlet, V., Roussel, A.M., Berr, C., 2005.
Selenium and mortality in the elderly: results from the EVA study. Clinical
Chemistry 51, 2117–2123.
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
15
Akbaraly, T.N., Hininger-Favier, I., Carriere, I., Arnaud, J., Gourlet, V., Roussel, A.M.,
Berr, C., 2007. Plasma selenium over time and cognitive decline in the elderly.
Epidemiology 18, 52–58.
Akbaraly, T.N., Arnaud, J., Rayman, M.P., Hininger-Favier, I., Roussel, A.M., Berr, C.,
Fontbonne, A., 2010. Plasma selenium and risk of dysglycemia in an elderly
French population: results from the prospective Epidemiology of Vascular
Ageing Study. Nutrition and Metabolism 7 , 21-7075-27.
Alanne, M., Kristiansson, K., Auro, K., Silander, K., Kuulasmaa, K., Peltonen, L.,
Salomaa, V., Perola, M., 2007. Variation in the selenoprotein S gene locus is
associated with coronary heart disease and ischemic stroke in two independent
Finnish cohorts. Human Genetics 122 (3–4) 355–365.
Alberti, S., Cevenini, E., Ostan, R., Capri, M., Salvioli, S., Bucci, L., Ginaldi, L., De
Martinis, M., Franceschi, C., Monti, D., 2006. Age-dependent modifications of
Type 1 and Type 2 cytokines within virgin and memory CD4+ T cells in humans.
Mechanisms of Ageing and Development 127, 560–566.
Alberts, M.J., Graffagnino, C., McClenny, C., DeLong, D., Strittmatter, W., Saunders,
A.M., Roses, A.D., 1995. ApoE genotype and survival from intracerebral hae-
morrhage. Lancet 346, 575.
Alvarez Leon, E., Henriquez, P., Serra-Majem, L., 2006. Mediterranean diet and
metabolic syndrome: a cross-sectional study in the Canary Islands. Public
Health Nutrition 9, 1089–1098.
Ames, B.N., 2006. Low micronutrient intake may accelerate the degenerative
diseases of aging through allocation of scarce micronutrients by triage. Pro-
ceedings of the National Academy of Sciences of the United States of America
103, 17589–17594.
Anantharaju, A., Feller, A., Chedid, A., 2002. Aging liver. A review. Gerontology 48,
343–353.
Andree, K.B., Kim, J., Kirschke, C.P., Gregg, J.P., Paik, H., Joung, H., Woodhouse, L.,
King, J.C., Huang, L., 2004. Investigation of lymphocyte gene expression for use
as biomarkers for zinc state in humans. The Journal of Nutrition 134, 1716–
1723.
Andreini, C., Bertini, I., 2012. A bioinformatics view of zinc enzymes. Journal of
Inorganic Biochemistry 111, 150–156.
Andrews, G.K., 2001. Cellular zinc sensors: MTF-1 regulation of gene expression.
Biometals 14, 223–237.
AREDS (Age-Related Eye Disease Study Research Group), 2001. A randomized,
placebo-controlled, clinical trial of high-dose supplementation with vita-
mins C and E, beta carotene, and zinc for age-related macular degeneration
and vision loss: AREDS report no. 8. Archives of Ophthalmology 119, 1417–
1436.
Arnaud, J., Akbaraly, T.N., Hininger, I., Roussel, A.M., Berr, C., 2007. Factors associated
with longitudinal plasma selenium decline in the elderly: the EVA study. The
Journal of Nutritional Biochemistry 18, 482–487.
Aro, A., Alfthan, G., Varo, P., 1995. Effects of supplementation of fertilizers on human
selenium status in Finland. The Analyst 120, 841–843.
Arredondo, M., Munoz, P., Mura, C.V., Nunez, M.T., 2003. DMT1, a physiologically
relevant apical Cu1+ transporter of intestinal cells. American Journal of Physi-
ology Cell Physiology 284, C1525–C1530.
G Model
MAD-10703; No. of Pages 21
16 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Bala, S., Failla, M.L., 1992. Copper deficiency reversibly impairs DNA synthesis in
activated T lymphocytes by limiting interleukin 2 activity. Proceedings of the
National Academy of Sciences of the United States of America 89, 6794–6797.
Bao, B., Prasad, A.S., Beck, F.W., Fitzgerald, J.T., Snell, D., Bao, G.W., Singh, T., Cardozo,
L.J., 2010. Zinc decreases C-reactive protein, lipid peroxidation, and inflamma-
tory cytokines in elderly subjects: a potential implication of zinc as an ather-
oprotective agent. The American Journal of Clinical Nutrition 91, 1634–1641.
Bareggi, S.R., Cornelli, U., 2012. Clioquinol: review of its mechanisms of action and
clinical uses in neurodegenerative disorders. CNS Neuroscience and Therapeu-
tics 18, 41–46.
Bayer, T.A., Schafer, S., Simons, A., Kemmling, A., Kamer, T., Tepest, R., Eckert, A.,
Schussel, K., Eikenberg, O., Sturchler-Pierrat, C., Abramowski, D., Staufenbiel, M.,
Multhaup, G., 2003. Dietary Cu stabilizes brain superoxide dismutase 1 activity
and reduces amyloid Abeta production in APP23 transgenic mice. Proceedings
of the National Academy of Sciences of the United States of America 100,
14187–14192.
Beck, M.A., 1999. Selenium and host defence towards viruses. The Proceedings of
the Nutrition Society 58, 707–711.
Beck, M.A., Kolbeck, P.C., Rohr, L.H., Shi, Q., Morris, V.C., Levander, O.A., 1994. Benign
human enterovirus becomes virulent in selenium-deficient mice. Journal of
Medical Virology 43, 166–170.
Beck, F.W., Prasad, A.S., Kaplan, J., Fitzgerald, J.T., Brewer, G.J., 1997. Changes in
cytokine production and T cell subpopulations in experimentally induced zinc-
deficient humans. The American Journal of Physiology 272, E1002–E1007.
Beck, M.A., Esworthy, R.S., Ho, Y.S., Chu, F.F., 1998. Glutathione peroxidase protects
mice from viral-induced myocarditis. FASEB Journal 12, 1143–1149.
Behne, D., Hammel, C., Pfeifer, H., Rothlein, D., Gessner, H., Kyriakopoulos, A., 1998.
Speciation of selenium in the mammalian organism. The Analyst 123, 871–873.
Bermano, G., Pagmantidis, V., Holloway, N., Kadri, S., Mowat, N.A., Shiel, R.S., Arthur,
J.R., Mathers, J.C., Daly, A.K., Broom, J., Hesketh, J.E., 2007. Evidence that a
polymorphism within the 3’UTR of glutathione peroxidase 4 is functional and is
associated with susceptibility to colorectal cancer. Genes and Nutrition 2, 225–
232.
Bleys, J., Navas-Acien, A., Guallar, E., 2007. Serum selenium and diabetes in US
adults. Diabetes Care 30, 829–834.
Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W., Dawsey, S.M., Li, B., 1995. The Linxian trials:
mortality rates by vitamin-mineral intervention group. The American Journal of
Clinical Nutrition 62, 1424S–1426S.
Bonham, M., O’Connor, J.M., Hannigan, B.M., Strain, J.J., 2002. The immune system as
a physiological indicator of marginal copper status? The British Journal of
Nutrition 87, 393–403.
Bossy-Wetzel, E., Talantova, M.V., Lee, W.D., Scholzke, M.N., Harrop, A., Mathews, E.,
Gotz, T., Han, J., Ellisman, M.H., Perkins, G.A., Lipton, S.A., 2004. Crosstalk
between nitric oxide and zinc pathways to neuronal cell death involving
mitochondrial dysfunction and p38-activated K+ channels. Neuron 41, 351–
365.
Brewer, G.J., 2007. Iron and copper toxicity in diseases of aging, particularly
atherosclerosis and Alzheimer’s disease. Experimental Biology and Medicine
232, 323–335.
Brewer, G.J., 2008. The risks of free copper in the body and the development of
useful anticopper drugs. Current Opinion in Clinical Nutrition and Metabolic
Care 11, 727–732.
Brewer, G.J., Askari, F., Dick, R.B., Sitterly, J., Fink, J.K., Carlson, M., Kluin, K.J., Lorincz,
M.T., 2009. Treatment of Wilson’s disease with tetrathiomolybdate: V. Control
of free copper by tetrathiomolybdate and a comparison with trientine. Trans-
lational Research 154, 70–77.
Brigelius-Flohe, R., Banning, A., 2006. Part of the series: from dietary antioxidants to
regulators in cellular signaling and gene regulation. Sulforaphane and selenium,
partners in adaptive response and prevention of cancer. Free Radical Research
40, 775–787.
Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R., Cox, D.W., 1993. The Wilson
disease gene is a putative copper transporting P-type ATPase similar to the
Menkes gene. Nature Genetics 5, 327–337.
Bush, A.I., 2000. Metals and neuroscience. Current Opinion in Chemical Biology 4,
184–191.
Camakaris, J., Danks, D.M., Ackland, L., Cartwright, E., Borger, P., Cotton, R.G., 1980.
Altered copper metabolism in cultured cells from human Menkes’ syndrome
and mottled mouse mutants. Biochemical Genetics 18, 117–131.
Casadei, M., Persichini, T., Polticelli, F., Musci, G., Colasanti, M., 2008. S-Glutathio-
nylation of metallothioneins by nitrosative/oxidative stress. Experimental
Gerontology 43, 415–422.
Chasapis, C.T., Loutsidou, A.C., Spiliopoulou, C.A., Stefanidou, M.E., 2012. Zinc and
human health: an update. Archives of Toxicology 86, 521–534.
Chernoff, R., 2001. Nutrition and health promotion in older adults. The Journals of
Gerontology Series A 56 (Spec. no. 2) 47–53.
Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A.,
Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y., Huang, X., Goldstein, L.E., Moir,
R.D., Lim, J.T., Beyreuther, K., Zheng, H., Tanzi, R.E., Masters, C.L., Bush, A.I., 2001.
Treatment with a copper–zinc chelator markedly and rapidly inhibits beta-
amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30, 665–
676.
Chiricolo, M., Musa, A.R., Monti, D., Zannotti, M., Franceschi, C., 1993. Enhanced DNA
repair in lymphocytes of Down syndrome patients: the influence of zinc
nutritional supplementation. Mutation Research 295, 105–111.
Chow, C.K., 1979. Nutritional influence on cellular antioxidant defense systems. The
American Journal of Clinical Nutrition 32, 1066–1081.
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
Cipriano, C., Malavolta, M., Costarelli, L., Giacconi, R., Muti, E., Gasparini, N., Cardelli,
M., Monti, D., Mariani, E., Mocchegiani, E., 2006. Polymorphisms in MT1a gene
coding region are associated with longevity in Italian Central female population.
Biogerontology 7, 357–365.
Combs, Jr., G.F., Combs, S.B. (Eds.), 1986. The Role of Selenium in Nutrition.
Academic Press, San Diego, CA, USA, pp. 1–210.
Cooper, G.J., Phillips, A.R., Choong, S.Y., Leonard, B.L., Crossman, D.J., Brunton,
D.H., Saafi, Dissanayake, A.M., Cowan, B.R., Young, A.A., Occleshaw, C.J.,
Chan, Y.K., Leahy, F.E., Keogh, G.F., Gamble, G.D., Allen, G.R., Pope, A.J.,
Boyd, P.D., Poppitt, S.D., Borg, T.K., Doughty, R.N., Baker, J.R., 2004. Regen-
eration of the heart in diabetes by selective copper chelation. Diabetes 53,
2501–2508.
Cooper, M.L., Adami, H.O., Gronberg, H., Wiklund, F., Green, F.R., Rayman, M.P., 2008.
Interaction between single nucleotide polymorphisms in selenoprotein P and
mitochondrial superoxide dismutase determines prostate cancer risk. Cancer
Research 68, 10171–10177.
Cossack, Z.T., 1989. T-lymphocyte dysfunction in the elderly associated with zinc
deficiency and subnormal nucleoside phosphorylase activity: effect of zinc
supplementation. European Journal of Cancer and Clinical Oncology 25, 973–
976.
Cousins, R.J., 1985. Absorption, transport, and hepatic metabolism of copper and
zinc: special reference to metallothionein and ceruloplasmin. Physiological
Reviews 65, 238–309.
Cousins, R.J., 1986. Toward a molecular understanding of zinc metabolism. Clinical
Physiology and Biochemistry 4, 20–30.
Cousins, R.J., 1998. A role of zinc in the regulation of gene expression. The
Proceedings of the Nutrition Society 57, 307–311.
Coyle, P., Philcox, J.C., Carey, L.C., Rofe, A.M., 2002. Metallothionein: the multipur-
pose protein. Cellular and Molecular Life Sciences 59, 627–647.
Cuajungco, M.P., Goldstein, L.E., Nunomura, A., Smith, M.A., Lim, J.T., Atwood, C.S.,
Huang, X., Farrag, Y.W., Perry, G., Bush, A.I., 2000. Evidence that the beta-
amyloid plaques of Alzheimer’s disease represent the redox-silencing and
entombment of abeta by zinc. The Journal of Biological Chemistry 275,
19439–19442.
Culotta, V.C., Lin, S.J., Schmidt, P., Klomp, L.W., Casareno, R.L., Gitlin, J., 1999.
Intracellular pathways of copper trafficking in yeast and humans. Advances
in Experimental Medicine and Biology 448, 247–254.
Curran, J.E., Jowett, J.B., Elliott, K.S., Gao, Y., Gluschenko, K., Wang, J., Abel Azim, D.M.,
Cai, G., Mahaney, M.C., Comuzzie, A.G., Dyer, T.D., Walder, K.R., Zimmet, P.,
MacCluer, J.W., Collier, G.R., Kissebah, A.H., Blangero, J., 2005. Genetic variation
in selenoprotein S influences inflammatory response. Nature Genetics 37,
1234–1241.
Czernichow, S., Bertrais, S., Blacher, J., Galan, P., Briancon, S., Favier, A., Safar, M.,
Hercberg, S., 2005. Effect of supplementation with antioxidants upon long-term
risk of hypertension in the SU.VI.MAX study: association with plasma antioxi-
dant levels. Journal of Hypertension 23, 2013–2018.
Dancis, A., Haile, D., Yuan, D.S., Klausner, R.D., 1994. The Saccharomyces cerevisiae
copper transport protein (Ctr1p). Biochemical characterization, regulation by
copper, and physiologic role in copper uptake. The Journal of Biological Chem-
istry 269, 25660–25667.
Danks, D.M., 1988. Copper deficiency in humans. Annual Review of Nutrition 8,
235–257.
Danzeisen, R., Araya, M., Harrison, B., Keen, C., Solioz, M., Thiele, D., McArdle, H.J.,
2007. How reliable and robust are current biomarkers for copper status? The
British Journal of Nutrition 98, 676–683.
Darnton-Hill, I., Margetts, B., Deckelbaum, R., 2004. Public health nutrition and
genetics: implications for nutrition policy and promotion. The Proceedings of
the Nutrition Society 63, 173–185.
Das, H., Kumar, A., Lin, Z., Patino, W.D., Hwang, P.M., Feinberg, M.W., Majumder, P.K.,
Jain, M.K., 2006. Kruppel-like factor 2 (KLF2) regulates proinflammatory acti-
vation of monocytes. Proceedings of the National Academy of Sciences of the
United States of America 103, 6653–6658.
Delerive, P., Gervois, P., Fruchart, J.C., Staels, B., 2000. Induction of IkappaBalpha
expression as a mechanism contributing to the anti-inflammatory activities of
peroxisome proliferator-activated receptor-alpha activators. The Journal of
Biological Chemistry 275, 36703–36707.
Delmi, M., Rapin, C.H., Bengoa, J.M., Delmas, P.D., Vasey, H., Bonjour, J.P., 1990.
Dietary supplementation in elderly patients with fractured neck of the femur.
Lancet 335, 1013–1016.
Dreher, I., Jakobs, T.C., Kohrle, J., 1997. Cloning and characterization of the human
selenoprotein P promoter. Response of selenoprotein P expression to cytokines
in liver cells. The Journal of Biological Chemistry 272, 29364–29371.
Duchateau, J., Delepesse, G., Vrijens, R., Collet, H., 1981. Beneficial effects of oral zinc
supplementation on the immune response of old people. The American Journal
of Medicine 70, 1001–1004.
El Balkhi, S., Poupon, J., Trocello, J.M., Massicot, F., Woimant, F., Laprévote, O., 2010.
Human plasma copper proteins speciation by size exclusion chromatography
coupled to inductively coupled plasma mass spectrometry. Solutions for col-
umns calibration by sulfur detection. Analitical Chemistry 82, 6904–6910.
Ellis, S.E., Coffey, C.S., Mitchel Jr., E.F., Dittus, R.S., Griffin, M.R., 2003. Influenza- and
respiratory syncytial virus-associated morbidity and mortality in the nursing
home population. Journal of the American Geriatrics Society 51, 761–767.
El-Omar, E.M., Chow, W.H., Rabkin, C.S., 2001. Gastric cancer and H. pylori: host
genetics open the way. Gastroenterology 121, 1002–1004.
Enbergs, A., Dorszewski, A., Luft, M., Monnig, G., Kleemann, A., Schulte, H., Assmann,
G., Breithardt, G., Kerber, S., 1998. Failure to confirm ferritin and caeruloplasmin
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
as risk factors for the angiographic extent of coronary arteriosclerosis. Coronary
Artery Disease 9, 119–124.
Erie, J.C., Good, J.A., Butz, J.A., Pulido, J.S., 2009. Reduced zinc and copper in the
retinal pigment epithelium and choroid in age-related macular degeneration.
American Journal of Ophthalmology 147, 276–282.e1.
Erusalimsky, J.D., Kurz, D.J., 2006. Endothelial cell senescence. Handbook of Experi-
mental Pharmacology 176 (Pt 2) 213–248.
Failla, M.L., 2003. Trace elements and host defense: recent advances and continuing
challenges. The Journal of Nutrition 133, 1443S–1447S.
Fan, A.M., Kizer, K.W., 1990. Selenium. Nutritional, toxicologic, and clinical aspects.
The Western Journal of Medicine 153, 160–167.
Faure, P., Ramon, O., Favier, A., Halimi, S., 2004. Selenium supplementation
decreases nuclear factor-kappa B activity in peripheral blood mononuclear
cells from type 2 diabetic patients. European Journal of Clinical Investigation
34, 475–481.
Ferns, G.A., Lamb, D.J., Taylor, A., 1997. The possible role of copper ions in athero-
genesis: the Blue Janus. Atherosclerosis 133, 139–152.
Festa, R.A., Thiele, D.J., 2011. Copper: an essential metal in biology. Current Biology
21, R877–R883.
Ford, E.S., 2000. Serum copper concentration and coronary heart disease among US
adults. American Journal of Epidemiology 151, 1182–1188.
Forsberg, L., de Faire, U., Marklund, S.L., Andersson, P.M., Stegmayr, B., Morgenstern,
R., 2000. Phenotype determination of a common Pro-Leu polymorphism in
human glutathione peroxidase 1. Blood Cells, Molecules and Diseases 26, 423–
426.
Fox, P.L., Mazumder, B., Ehrenwald, E., Mukhopadhyay, C.K., 2000. Ceruloplasmin
and cardiovascular disease. Free Radical Biology and Medicine 28, 1735–1744.
Fraker, P.J., King, L.E., 2001. A distinct role for apoptosis in the changes in lympho-
poiesis and myelopoiesis created by deficiencies in zinc. FASEB Journal 15,
2572–2578.
Fraker, P.J., King, L.E., 2004. Reprogramming of the immune system during zinc
deficiency. Annual Review of Nutrition 24, 277–298.
Franceschi, C., 2007. Inflammaging as a major characteristic of old people: can it be
prevented or cured? Nutrition Review 65, S173–S176.
Franceschi, C., Chiricolo, M., Licastro, F., Zannotti, M., Masi, M., Mocchegiani, E.,
Fabris, N., 1988. Oral zinc supplementation in Down’s syndrome: restoration of
thymic endocrine activity and of some immune defects. Journal of Mental
Deficiency Research 32 (Pt 3) 169–181.
Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De
Benedictis, G., 2000. Inflamm-aging. An evolutionary perspective on immuno-
senescence. Annals of the New York Academy of Sciences 908, 244–254.
Frazzini, V., Rockabrand, E., Mocchegiani, E., Sensi, S.L., 2006. Oxidative stress and
brain aging: is zinc the link? Biogerontology 7, 307–314.
Frederickson, C.J., Burdette, S.C., Frederickson, C.J., Sensi, S.L., Weiss, J.H., Yin, H.Z.,
Balaji, R.V., Truong-Tran, A.Q., Bedell, E., Prough, D.S., Lippard, S.J., 2004. Method
for identifying neuronal cells suffering zinc toxicity by use of a novel fluorescent
sensor. Journal of Neuroscience Medicine 139, 79–89.
Freisinger, P., Horvath, R., Macmillan, C., Peters, J., Jaksch, M., 2004. Reversion of
hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial
copper binding protein SCO2: is there a potential effect of copper? Journal of
Inherited Metabolic Disease 27, 67–79.
Fukuyama, S., Matsunaga, Y., Zhanghui, W., Noda, N., Asai, Y., Moriwaki, A., Matsu-
moto, T., Nakano, T., Matsumoto, K., Nakanishi, Y., Inoue, H., 2011. A zinc
chelator TPEN attenuates airway hyper responsiveness and airway inflamma-
tion in mice in vivo. Allergology International 60, 259–266.
Fulop Jr., T., Larbi, A., Dupuis, G., Pawelec, G., 2003. Ageing, autoimmunity and
arthritis: perturbations of TCR signal transduction pathways with ageing – a
biochemical paradigm for the ageing immune system. Arthritis Research and
Therapy 5, 290–302.
Funseth, E., Lindh, U., Wesslen, L., Friman, G., Ilback, N.G., 2000. Trace element
changes in the myocardium during coxsackievirus B3 myocarditis in the mouse.
Biological Trace Element Research 76, 149–160.
Gao, Y., Hannan, N.R., Wanyonyi, S., Konstantopolous, N., Pagnon, J., Feng, H.C.,
Jowett, J.B., Kim, K.H., Walder, K., Collier, G.R., 2006. Activation of the seleno-
protein SEPS1 gene expression by pro-inflammatory cytokines in HepG2 cells.
Cytokine 33, 246–251.
Giacconi, R., Cipriano, C., Muti, E., Costarelli, L., Maurizio, C., Saba, V., Gasparini, N.,
Malavolta, M., Mocchegiani, E., 2005. Novel 209A/G MT2A polymorphism in
old patients with type 2 diabetes and atherosclerosis: relationship with inflam-
mation (IL-6) and zinc. Biogerontology 6, 407–413.
Giacconi, R., Bonfigli, A.R., Testa, R., Sirolla, C., Cipriano, C., Marra, M., Muti, E.,
Malavolta, M., Costarelli, L., Piacenza, F., Tesei, S., Mocchegiani, E., 2008a. +647
A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus
and cardiovascular complications. Molecular Genetics and Metabolism 94, 98–
104.
Giacconi, R., Muti, E., Malavolta, M., Cardelli, M., Pierpaoli, S., Cipriano, C., Costarelli,
L., Tesei, S., Saba, V., Mocchegiani, E., 2008b. A novel Zip2 Gln/Arg/Leu codon 2
polymorphism is associated with carotid artery disease in aging. Rejuvenation
Research 11, 297–300.
Giacconi, R., Kanoni, S., Mecocci, P., Malavolta, M., Richter, D., Pierpaoli, S., Costarelli,
L., Cipriano, C., Muti, E., Mangialasche, F., Piacenza, F., Tesei, S., Galeazzi, R.,
Theodoraki, E.V., Lattanzio, F., Dedoussis, G., Mocchegiani, E., 2010. Association
of MT1A haplotype with cardiovascular disease and antioxidant enzyme de-
fense in elderly Greek population: comparison with an Italian cohort. The
Journal of Nutritional Biochemistry 21, 1008–1014.
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
17
Girodon, F., Galan, P., Monget, A.L., Boutron-Ruault, M.C., Brunet-Lecomte, P.,
Preziosi, P., Arnaud, J., Manuguerra, J.C., Herchberg, S., 1999. Impact of trace
elements and vitamin supplementation on immunity and infections in institu-
tionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX.
geriatric network. Archives of Internal Medicine 159, 748–754.
Gojová, L., Jansova, E., Kulm, M., Pouchla, S., Kozak, L., 2008. Genotyping microarray
as a novel approach for the detection of ATP7B gene mutations in patients with
Wilson disease. Clinical Genetics 73, 441–452.
Golovine, K., Uzzo, R.G., Makhov, P., Crispen, P.L., Kunkle, D., Kolenko, V.M., 2008.
Depletion of intracellular zinc increases expression of tumorigenic cytokines
VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kappaB-dependent pathway.
Prostate 68, 1443–1449.
Gonzalez, S., Huerta, J.M., Fernandez, S., Patterson, A.M., Lasheras, C., 2007. Life-
quality indicators in elderly people are influenced by selenium status. Aging
Clinical and Experimental Research 19, 10–15.
Guo, C.H., Wang, C.L., 2013. Effects of zinc supplementation on plasma copper/zinc
ratios, oxidative stress, and immunological status in hemodialysis patients.
International Journal of Medical Sciences 10, 79–89.
Haase, H., Rink, L., 2009a. Functional significance of zinc-related signaling pathways
in immune cells. Annual Review of Nutrition 29, 133–152.
Haase, H., Rink, L., 2009b. The immune system and the impact of zinc during aging.
Immunity and Ageing 6, 6–9.
Haase, H., Ober-Blobaum, J.L., Engelhardt, G., Hebel, S., Heit, A., Heine, H., Rink, L.,
2008. Zinc signals are essential for lipopolysaccharide-induced signal transduc-
tion in monocytes. Journal of Immunology 181, 6491–6502.
Hamza, I., Faisst, A., Prohaska, J., Chen, J., Gruss, P., Gitlin, J.D., 2001. The metallo-
chaperone Atox1 plays a critical role in perinatal copper homeostasis. Proceed-
ings of the National Academy of Sciences of the United States of America 98,
6848–6852.
Hamza, I., Prohaska, J., Gitlin, J.D., 2003. Essential role for Atox1 in the copper-
mediated intracellular trafficking of the Menkes ATPase. Proceedings of the
National Academy of Sciences of the United States of America 100, 1215–1220.
Hartmann, H.J., Felix, K., Nagel, W., Weser, U., 1993. Intestinal administration of
copper and its transient release into venous rat blood serum concomitantly
with metallothionein. Biometals 6, 115–118.
Harvey, L.J., Majsak-Newman, G., Dainty, J.R., Lewis, D.J., Langford, N.J., Crews, H.M.,
Fairweather-Tait, S.J., 2003. Adaptive responses in men fed low- and high-
copper diets. The British Journal of Nutrition 90, 161–168.
Harvey, L.J., Ashton, K., Hooper, L., Casgrain, A., Fairweather-Tait, S.J., 2009. Methods
of assessment of copper status in humans: a systematic review. The American
Journal of Clinical Nutrition 89, 2009S–2024S.
Hatfield, D.L., Gladyshev, V.N., 2002. How selenium has altered our understanding
of the genetic code. Molecular and Cellular Biology 22, 3565–3576.
Hayden, M.S., Ghosh, S., 2008. Shared principles in NF-kappaB signaling. Cell 132,
344–362.
Hayes, J.D., McLellan, L.I., 1999. Glutathione and glutathione-dependent enzymes
represent a co-ordinately regulated defence against oxidative stress. Free
Radical Research 31, 273–300.
Hesketh, J., 2008. Nutrigenomics and selenium: gene expression patterns, physio-
logical targets, and genetics. Annual Review of Nutrition 28, 157–177.
Hesketh, J., Meplan, C., 2011. Transcriptomics and functional genetic polymor-
phisms as biomarkers of micronutrient function: focus on selenium as an
exemplar. The Proceedings of the Nutrition Society 70, 1–9.
Hopkins, R.G., Failla, M.L., 1999. Transcriptional regulation of interleukin-2 gene
expression is impaired by copper deficiency in Jurkat human T lymphocytes.
The Journal of Nutrition 129, 596–601.
Hu, Y.J., Diamond, A.M., 2003. Role of glutathione peroxidase 1 in breast cancer: loss
of heterozygosity and allelic differences in the response to selenium. Cancer
Research 63, 3347–3351.
Hu, Y.J., Korotkov, K.V., Mehta, R., Hatfield, D.L., Rotimi, C.N., Luke, A., Prewitt, T.E.,
Cooper, R.S., Stock, W., Vokes, E.E., Dolan, M.E., Gladyshev, V.N., Diamond, A.M.,
2001. Distribution and functional consequences of nucleotide polymorphisms
in the 30 -untranslated region of the human Sep15 gene. Cancer Research 61,
2307–2310.
Ichimura, Y., Habuchi, T., Tsuchiya, N., Wang, L., Oyama, C., Sato, K., Nishiyama, H.,
Ogawa, O., Kato, T., 2004. Increased risk of bladder cancer associated with a
glutathione peroxidase 1 codon 198 variant. The Journal of Urology 172, 728–
732.
Jablonska, E., Gromadzinska, J., Sobala, W., Reszka, E., Wasowicz, W., 2008. Lung
cancer risk associated with selenium status is modified in smoking individuals
by Sep15 polymorphism. European Journal of Nutrition 47, 47–54.
Jiang, Y., Reynolds, C., Xiao, C., Feng, W., Zhou, Z., Rodriguez, W., Tyagi, S.C., Eaton,
J.W., Saari, J.T., Kang, Y.J., 2007. Dietary copper supplementation reverses
hypertrophic cardiomyopathy induced by chronic pressure overload in mice.
The Journal of Experimental Medicine 204, 657–666.
Kabu, K., Yamasaki, S., Kamimura, D., Ito, Y., Hasegawa, A., Sato, E., Kitamura, H.,
Nishida, K., Hirano, T., 2006. Zinc is required for Fc epsilon RI-mediated mast cell
activation. Journal of Immunology 177, 1296–1305.
Kahmann, L., Uciechowski, P., Warmuth, S., Plumakers, B., Gressner, A.M., Malavolta,
M., Mocchegiani, E., Rink, L., 2008. Zinc supplementation in the elderly reduces
spontaneous inflammatory cytokine release and restores T cell functions.
Rejuvenation Research 11, 227–237.
Kaler, S.G., 1994. Menkes disease. Advances in Pediatrics 41, 263–304.
Kant, A.K., 2000. Consumption of energy-dense, nutrient-poor foods by adult
Americans: nutritional and health implications. The third National Health
G Model
MAD-10703; No. of Pages 21
18 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
and Nutrition Examination Survey, 1988–1994. The American Journal of Clinical
Nutrition 72, 929–936.
Kato, K., Oguri, M., Kato, N., Hibino, T., Yajima, K., Yoshida, T., Metoki, N., Yoshida, H.,
Satoh, K., Watanabe, S., Yokoi, K., Murohara, T., Yamada, Y., 2008. Assessment of
genetic risk factors for thoracic aortic aneurysm in hypertensive patients.
American Journal of Hypertension 21, 1023–1027.
Kelley, D.S., Daudu, P.A., Taylor, P.C., Mackey, B.E., Turnlund, J.R., 1995. Effects of
low-copper diets on human immune response. The American Journal of Clinical
Nutrition 62, 412–416.
Kelner, G.S., Lee, M., Clark, M.E., Maciejewski, D., McGrath, D., Rabizadeh, S., Lyons,
T., Bredesen, D., Jenner, P., Maki, R.A., 2000. The copper transport protein Atox1
promotes neuronal survival. The Journal of Biological Chemistry 275, 580–584.
Khatai, L., Goessler, W., Lorencova, H., Zangger, K., 2004. Modulation of nitric oxide-
mediated metal release from metallothionein by the redox state of glutathione
in vitro. European Journal of Biochemistry 271, 2408–2416.
Kim, Y.S., Milner, J., 2001. Molecular targets for selenium in cancer prevention.
Nutrition and Cancer 40, 50–54.
Kim, C.H., Park, J.Y., Kim, J.Y., Choi, C.S., Kim, Y.I., Chung, Y.E., Lee, M.S., Hong, S.K.,
Lee, K.U., 2002. Elevated serum ceruloplasmin levels in subjects with metabolic
syndrome: a population-based study. Metabolism: Clinical and Experimental
51, 838–842.
Kipp, A., Banning, A., van Schothorst, E.M., Meplan, C., Schomburg, L., Evelo, C., Coort,
S., Gaj, S., Keijer, J., Hesketh, J., Brigelius-Flohe, R., 2009. Four selenoproteins,
protein biosynthesis, and Wnt signalling are particularly sensitive to limited
selenium intake in mouse colon. Molecular Nutrition and Food Research 53,
1561–1572.
Kirchman, P.A., Botta, G., 2007. Copper supplementation increases yeast life span
under conditions requiring respiratory metabolism. Mechanisms of Ageing and
Development 128, 187–195.
Klevay, L.M., 2000. Cardiovascular disease from copper deficiency – a history. The
Journal of Nutrition 130, 489S–492S.
Klipstein-Grobusch, K., Grobbee, D.E., Koster, J.F., Lindemans, J., Boeing, H., Hofman,
A., Witteman, J.C., 1999. Serum caeruloplasmin as a coronary risk factor in the
elderly: the Rotterdam Study. The British Journal of Nutrition 81, 139–144.
Klug, A., 1999. Zinc finger peptides for the regulation of gene expression. Journal of
Molecular Biology 293, 215–218.
Krajacic, P., Qian, Y., Hahn, P., Dentchev, T., Lukinova, N., Dunaief, J.L., 2006. Retinal
localization and copper-dependent relocalization of the Wilson and Menkes
disease proteins. Investigative Ophthalmology and Visual Science 47, 3129–
3134.
Kreuder, J., Otten, A., Fuder, H., Tümer, Z., Tønnesen, T., Horn, N., Dralle, D., 1993.
Clinical and biochemical consequences of copper–histidine therapy in Menkes
disease. European Journal of Pediatrics 152, 828–832.
Kryukov, G.V., Castellano, S., Novoselov, S.V., Lobanov, A.V., Zehtab, O., Guigo, R.,
Gladyshev, V.N., 2003. Characterization of mammalian selenoproteomes. Sci-
ence 300, 1439–1443.
Kury, S., Dreno, B., Bezieau, S., Giraudet, S., Kharfi, M., Kamoun, R., Moisan, J.P., 2002.
Identification of SLC39A4, a gene involved in acrodermatitis enteropathica.
Nature Genetics 31, 239–240.
Lalioti, V., Muruais, G., Tsuchiya, Y., Pulido, D., Sandoval, I.V., 2009. Molecular
mechanisms of copper homeostasis. Frontiers in Bioscience 14, 4878–4903.
Lansdown, A.B., Mirastschijski, U., Stubbs, N., Scanlon, E., Agren, M.S., 2007. Zinc in
wound healing: theoretical, experimental, and clinical aspects. Wound Repair
and Regeneration 15, 2–16.
Lee, P.L., Gelbart, T., West, C., Halloran, C., Felitti, V., Beutler, E., 2001. A study of
genes that may modulate the expression of hereditary hemochromatosis:
transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy
chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood Cells,
Molecules and Diseases 27, 783–802.
Lee, J.Y., Kim, J.H., Palmiter, R.D., Koh, J.Y., 2003. Zinc released from metallothionein-
iii may contribute to hippocampal CA1 and thalamic neuronal death following
acute brain injury. Experimental Neurology 184, 337–347.
Li, Q., Liu, M., Hou, J., Jiang, C., Li, S., Wang, T., 2013. The prevalence of Keshan disease
in China. International Journal of Cardiology 168, 1121–1126.
Linder, M.C., Hazegh-Azam, M., 1996. Copper biochemistry and molecular biology.
The American Journal of Clinical Nutrition 63, 797S–811S.
Lippman, S.M., Klein, E.A., Goodman, P.J., Lucia, M.S., Thompson, I.M., Ford, L., Parnes,
G., Minasian, H.L., Gaziano, L.M., Hartline, J.M., Parsons, J.A., Bearden, J.K.,
Crawford 3rd, J.D., Goodman, E.D., Claudio, G.E., Winquist, J., Cook, E., Karp,
E.D., Walther, D.D., Lieber, P., Kristal, M.M., Darke, A.R., Arnold, A.K., Ganz, K.B.,
Santella, P.A., Albanes, R.M., Taylor, D., Probstfield, P.R., Jagpal, J.L., Crowley, T.J.,
Meyskens Jr., J.J., Baker, F.L., Coltman Jr., L.H.C.A., 2009. Effect of selenium and
vitamin E on risk of prostate cancer and other cancers: the Selenium and
Vitamin E Cancer Prevention Trial (SELECT). The Journal of the American
Medical Association 301, 39–51.
Liu, J., Atamna, H., Kuratsune, H., Ames, B.N., 2002. Delaying brain mitochondrial
decay and aging with mitochondrial antioxidants and metabolites. Annals of
the New York Academy of Sciences 959, 133–166.
Llanos, R.M., Mercer, J.F., 2002. The molecular basis of copper homeostasis copper-
related disorders. DNA and Cell Biology 21, 259–270.
Lowe, N.M., Lowe, N.M., Fraser, W.D., Jackson, M.J., 2002. Is there a potential
therapeutic value of copper and zinc for osteoporosis? The Proceedings of
the Nutrition Society 61, 181–185.
Lutsenko, S., Petris, M.J., 2003. Function and regulation of the mammalian copper-
transporting ATPases: insights from biochemical and cell biological approaches.
The Journal of Membrane Biology 191, 1–12.
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
Lyons, T.J., Nersissian, A., Huang, H., Yeom, H., Nishida, C.R., Graden, J.A., Gralla, E.B.,
Valentine, J.S., 2000. The metal binding properties of the zinc site of yeast
copper–zinc superoxide dismutase: implications for amyotrophic lateral scle-
rosis. Journal of Biological Inorganic Chemistry 5, 189–203.
Mackay, J.P., Crossley, M., 1998. Zinc fingers are sticking together. Trends in
Biochemical Science 23, 1–4.
Madarić, A., Ginter, E., Kadrabová, J., 1994. Serum copper, zinc and copper/zinc ratio
in males: influence of aging. Physiological Research 43, 107–111.
Maggini, S., Wintergerst, E.S., Beveridge, S., Hornig, D.H., 2007. Selected vitamins
and trace elements support immune function by strengthening epithelial
barriers and cellular and humoral immune responses. The British Journal of
Nutrition 98 (Suppl 1) S29–S35.
Malavolta, M., Giacconi, R., Piacenza, F., Santarelli, L., Cipriano, C., Costarelli, L.,
Tesei, S., Pierpaoli, S., Basso, A., Galeazzi, R., Lattanzio, F., Mocchegiani, E.,
2010. Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as
predictor of all-cause mortality in elderly population. Biogerontology 11,
309–319.
Malavolta, M., Piacenza, F., Basso, A., Giacconi, R., Costarelli, L., Pierpaoli, S.,
Mocchegiani, E., 2012. Speciation of trace elements in human serum by micro
anion exchange chromatography coupled with inductively coupled plasma
mass spectrometry. Analytical Biochemistry 421, 16–25.
Mao, X., Schimmer, A.D., 2008. The toxicology of Clioquinol. Toxicology Letters 182,
1–6.
Marcellini, F., Giuli, C., Papa, R., Gagliardi, C., Dedoussis, G., Monti, D., Jajte, J.,
Giacconi, R., Malavolta, M., Mocchegiani, E., 2008. Zinc in elderly people: effects
of zinc supplementation on psychological dimensions in dependence of IL-6
174 polymorphism: a Zincage study. Rejuvenation Research 11, 479–483.
Maret, W., 2003. Cellular zinc and redox states converge in the metallothionein/
thionein pair. The Journal of Nutrition 133 , 1460S-2S.
Maret, W., 2006. Zinc coordination environments in proteins as redox sensors and
signal transducers. Antioxidants and Redox Signalling 8, 1419–1441.
Mariani, E., Mangialasche, F., Feliziani, F.T., Cecchetti, R., Malavolta, M., Bastiani, P.,
Baglioni, M., Dedoussis, G., Fulop, T., Herbein, G., Jajte, J., Monti, D., Rink, L.,
Mocchegiani, E., Mecocci, P., 2008a. Effects of zinc supplementation on antioxi-
dant enzyme activities in healthy old subjects. Experimental Gerontology 43,
445–451.
Mariani, E., Neri, S., Cattini, L., Mocchegiani, E., Malavolta, M., Dedoussis, G.V.,
Kanoni, S., Rink, L., Jajte, J., Facchini, A., 2008b. Effect of zinc supplementation on
plasma IL-6 and MCP-1 production and NK cell function in healthy elderly:
interactive influence of +647 MT1a and 174 IL-6 polymorphic alleles. Experi-
mental Gerontology 43, 462–471.
Martin, J.E., Sheaff, M.T., 2007. Renal ageing. The Journal of Pathology 211, 198–205.
Mattie, M.D., Freedman, J.H., 2001. Protective effects of aspirin and vitamin E
(alpha-tocopherol) against copper- and cadmium-induced toxicity. Biochemi-
cal and Biophysical Research Communications 285, 921–925.
Mattson, M.P., 2008. Dietary factors, hormesis and health. Ageing Research Reviews
7, 43–48.
Mazzatti, D.J., Malavolta, M., White, A.J., Costarelli, L., Giacconi, R., Muti, E., Cipriano,
C., Powell, J.R., Mocchegiani, E., 2007. Differential effects of in vitro zinc
treatment on gene expression in peripheral blood mononuclear cells derived
from young and elderly individuals. Rejuvenation Research 10, 603–620.
Mehdi, Y., Hornick, J.L., Istasse, L., Dufrasne, I., 2013. Selenium in the environment,
metabolism and involvement in body functions. Molecules 18, 3292–3311.
Meplan, C., 2011. Trace elements and ageing, a genomic perspective using selenium
as an example. Journal of Trace Elements in Medicine and Biology 25 (Suppl 1)
S11–S16.
Meplan, C., Crosley, L.K., Nicol, F., Beckett, G.J., Howie, A.F., Hill, K.E., Horgan, G.,
Mathers, J.C., Arthur, J.R., Hesketh, J.E., 2007. Genetic polymorphisms in the
human selenoprotein P gene determine the response of selenoprotein markers
to selenium supplementation in a gender-specific manner (the SELGEN study).
FASEB Journal 21, 3063–3074.
Meplan, C., Crosley, L.K., Nicol, F., Horgan, G.W., Mathers, J.C., Arthur, J.R., Hesketh,
J.E., 2008. Functional effects of a common single-nucleotide polymorphism
(GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex. The
American Journal of Clinical Nutrition 87, 1019–1027.
Mercer, J.F., 2001. The molecular basis of copper-transport diseases. Trends in
Molecular Medicine 7, 64–69.
El Meskini, R., Culotta, V.C., Mains, R.E., Eipper, B.A., 2003. Supplying copper to the
cuproenzyme peptidylglycine alpha-amidating monooxygenase. The Journal of
Biological Chemistry 278, 12278–12284.
Meydani, M., 2001. Nutrition interventions in aging and age-associated disease.
Annals of the New York Academy of Science 928, 226L 235.
Meyer, F., Galan, P., Douville, P., Bairati, I., Kegle, P., Bertrais, S., Estaquio, C.,
Hercberg, S., 2005. Antioxidant vitamin and mineral supplementation and
prostate cancer prevention in the SU.VI.MAX trial. International Journal of
Cancer 116, 182–186.
Milne, D.B., 1998. Copper intake and assessment of copper status. The American
Journal of Clinical Nutrition 67, 1041S–1045S.
Mitchell, B.D., Hsueh, W.C., King, T.M., Pollin, T.I., Sorkin, J., Agarwala, R., Schaffer,
A.A., Shuldiner, A.R., 2001. Heritability of life span in the Old Order Amish.
American Journal of Medical Genetics 102, 346–352.
Mitchell, W.A., Meng, I., Nicholson, S.A., Aspinall, R., 2006. Thymic output ageing and
zinc. Biogerontology 7, 461–470.
Mitrou, P.N., Kipnis, V., Thiebaut, A.C., Reedy, J., Subar, A.F., Wirfalt, E., Flood, A.,
Mouw, T., Hollenbeck, A.R., Leitzmann, M.F., Schatzkin, A., 2007. Mediterranean
dietary pattern and prediction of all-cause mortality in a US population: results
G Model
MAD-10703; No. of Pages 21
E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
from the NIH-AARP Diet and Health Study. Archives of Internal Medicine 167,
2461–2468.
Miyata, M., Smith, J.D., 1996. Apolipoprotein E allele-specific antioxidant activity
and effects on cytotoxicity by oxidative insults and beta-amyloid peptides.
Nature Genetics 14, 55–61.
Mocchegiani, E., Malavolta, M., 2008b. Zinc–gene interaction related to inflamma-
tory/immune response in ageing. Genes and Nutrition 3, 61–75.
Mocchegiani, E., Giacconi, R., Muzzioli, M., Cipriano, C., 2000a. Zinc, infections and
immunosenescence. Mechanisms of Ageing and Development 121, 21–35.
Mocchegiani, E., Muzzioli, M., Giacconi, R., 2000b. Zinc and immunoresistance to
infection in aging: new biological tools. Trends in Pharmacological Sciences 21,
205–208.
Mocchegiani, E., Giacconi, R., Cipriano, C., Muzzioli, M., Gasparini, N., Moresi, R.,
Stecconi, R., Suzuki, H., Cavalieri, E., Mariani, E., 2002. MtmRNA gene expression,
via IL-6 and glucocorticoids, as potential genetic marker of immunosenescence:
lessons from very old mice and humans. Experimental Gerontology 37, 349–
357.
Mocchegiani, E., Muzzioli, M., Giacconi, R., Cipriano, C., Gasparini, N., Franceschi, C.,
Gaetti, R., Cavalieri, E., Suzuki, H., 2003. Metallothioneins/PARP-1/IL-6 interplay
on natural killer cell activity in elderly: parallelism with nonagenarians and old
infected humans. Effect of zinc supply. Mechanisms of Ageing and Development
124, 459–468.
Mocchegiani, E., Bertoni-Freddari, C., Marcellini, F., Malavolta, M., 2005. Brain, aging
and neurodegeneration: role of zinc ion availability. Progress in Neurobiology
75, 367–390.
Mocchegiani, E., Costarelli, L., Giacconi, R., Cipriano, C., Muti, E., Malavolta, M.,
2006a. Zinc-binding proteins (metallothionein and alpha-2 macroglobulin) and
immunosenescence. Experimental Gerontology 41, 1094–1107.
Mocchegiani, E., Costarelli, L., Giacconi, R., Cipriano, C., Muti, E., Tesei, S., Malavolta,
M., 2006b. Nutrient-gene interaction in ageing and successful ageing. A single
nutrient (zinc) and some target genes related to inflammatory/immune re-
sponse. Mechanisms of Ageing and Development 127, 517–525.
Mocchegiani, E., Giacconi, R., Cipriano, C., Costarelli, L., Muti, E., Tesei, S., Giuli, C.,
Papa, R., Marcellini, F., Mariani, E., Rink, L., Herbein, G., Varin, A., Fulop, T., Monti,
D., Jajte, J., Dedoussis, G., Gonos, E.S., Trougakos, I.P., Malavolta, M., 2007. Zinc
metallothioneins and longevity – effect of zinc supplementation: Zincage study.
Annals of the New York Academy of Sciences 1119, 129–146.
Mocchegiani, E., Giacconi, R., Costarelli, L., Muti, E., Cipriano, C., Tesei, S., Pierpaoli, S.,
Giuli, C., Papa, R., Marcellini, F., Gasparini, N., Pierandrei, R., Piacenza, F., Mariani,
E., Monti, D., Dedoussis, G., Kanoni, S., Herbein, G., Fulop, T., Rink, L., Jajte, J.,
Malavolta, M., 2008a. Zinc deficiency and IL-6 174G/C polymorphism in old
people from different European countries: effect of zinc supplementation.
ZINCAGE study. Experimental Gerontology 43, 433–444.
Mocchegiani, E., Malavolta, M., Muti, E., Costarelli, L., Cipriano, C., Piacenza, F., Tesei,
S., Giacconi, R., Lattanzio, F., 2008c. Zinc, metallothioneins and longevity:
interrelationships with niacin and selenium. Current Pharmaceutical Design
14, 2719–2732.
Mocchegiani, E., Giacconi, R., Cipriano, C., Malavolta, M., 2009. NK and NKT cells in
aging and longevity: role of zinc and metallothioneins. Journal of Clinical
Immunology 29, 416–425.
Mocchegiani, E., Costarelli, L., Giacconi, R., Piacenza, F., Basso, A., Malavolta, M.,
2012a. Micronutrient (Zn, Cu, Fe)–gene interactions in ageing and inflammatory
age-related diseases: implications for treatments. Ageing Research Reviews 11,
297–319.
Mocchegiani, E., Malavolta, M., Lattanzio, F., Piacenza, F., Basso, A., Abbatecola, A.M.,
Russo, A., Giovannini, S., Capoluongo, E., Bustacchini, S., Guffanti, E.E., Bernabei,
R., Landi, F., 2012b. Cu to Zn ratio, physical function, disability, and mortality
risk in older elderly (ilSIRENTE study). Age 34, 539–552.
Mocchegiani, E., Costarelli, L., Basso, A., Giacconi, R., Piacenza, F., Malavolta, M.,
2013a. Metallothioneins, ageing and cellular senescence: a future therapeutic
target. Current Pharmaceutical Design 19, 1753–1764.
Mocchegiani, E., Romeo, J., Malavolta, M., Costarelli, L., Giacconi, R., Diaz, L.E.,
Marcos, A., 2013b. Zinc: dietary intake and impact of supplementation on
immune function in elderly. Age 35, 839–860.
Moroni, F., Di Paolo, M.L., Rigo, A., Cipriano, C., Giacconi, R., Recchioni, R., March-
eselli, F., Malavolta, M., Mocchegiani, E., 2005. Interrelationship among neutro-
phil efficiency, inflammation, antioxidant activity and zinc pool in very old age.
Biogerontology 6, 271–281.
Moulder, K., Steward, M.W., 1989. Experimental zinc deficiency: effects on cellular
responses and the affinity of humoral antibody. Clinical and Experimental
Immunology 77, 269–274.
Mukhopadhyay, C.K., Mazumder, B., Lindley, P.F., Fox, P.L., 1997. Identification of the
prooxidant site of human ceruloplasmin: a model for oxidative damage by
copper bound to protein surfaces. Proceedings of the National Academy of
Sciences of the United States of America 94, 11546–11551.
Multhaup, G., Schlicksupp, A., Hesse, L., Beher, D., Ruppert, T., Masters, C.L., Beyr-
euther, K., 1996. The amyloid precursor protein of Alzheimer’s disease in the
reduction of copper(II) to copper(I). Science 271, 1406–1409.
Muñoz, C., Rios, E., Olivos, J., Brunser, O., Olivares, M., 2007. Iron, copper and
immunocompetence. British Journal of Nutrition 98 (Suppl 1) S24–S28.
Nasi, M., Troiano, L., Lugli, E., Pinti, M., Ferraresi, R., Monterastelli, E., Mussi, C.,
Salvioli, G., Franceschi, C., Cossarizza, A., 2006. Thymic output and functionality
of the IL-7/IL-7 receptor system in centenarians: implications for the neolym-
phogenesis at the limit of human life. Aging Cell 5, 167–175.
Nawrot, T.S., Staessen, J.A., Roels, H.A., Den Hond, E., Thijs, L., Fagard, R.H., Domin-
iczak, A.F., Struijker-Boudier, H.A., 2007. Blood pressure and blood selenium: a
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
19
cross-sectional and longitudinal population study. European Heart Journal 28,
628–633.
Nelson, T.J., Alkon, D.L., 2005. Oxidation of cholesterol by amyloid precursor protein
and beta-amyloid peptide. The Journal of Biological Chemistry 280, 7377–7387.
Nicolas, M.G., Fujiki, K., Murayama, K., Suzuki, M.T., Shindo, N., Hotta, Y., Iwata, F.,
Fujimura, T., Yoshikawa, Y., Cho, F., Kanai, A., 1996. Studies on the mechanism of
early onset macular degeneration in cynomolgus monkeys. II. Suppression of
metallothionein synthesis in the retina in oxidative stress. Experimental Eye
Research 62, 399–408.
Odumade, O.A., Weinreich, M.A., Jameson, S.C., Hogquist, K.A., 2010. Krüppel-like
factor 2 regulates trafficking and homeostasis of gammadelta T cells. Journal of
Immunology 184, 6060–6066.
Olivares, M., Uauy, R., 1996. Copper as an essential nutrient. The American Journal of
Clinical Nutrition 63, 791S–796S.
Olivieri, O., Girelli, D., Stanzial, A.M., Rossi, L., Bassi, A., Corrocher, R., 1996. Selenium,
zinc, and thyroid hormones in healthy subjects: low T3/T4 ratio in the elderly is
related to impaired selenium status. Biological Trace Element Research 51, 31–
41.
Osaki, S., Johnson, D.A., 1969. Mobilization of liver iron by ferroxidase (ceruloplas-
min). The Journal of Biological Chemistry 244, 5757–5758.
Pagmantidis, V., Meplan, C., van Schothorst, E.M., Keijer, J., Hesketh, J.E., 2008.
Supplementation of healthy volunteers with nutritionally relevant amounts of
selenium increases the expression of lymphocyte protein biosynthesis genes.
The American Journal of Clinical Nutrition 87, 181–189.
Pajonk, F.G., Kessler, H., Supprian, T., Hamzei, P., Bach, D., Schweickhardt, J.,
Herrmann, W., Obeid, R., Simons, A., Falkai, P., Multhaup, G., Bayer, T.A.,
2005. Cognitive decline correlates with low plasma concentrations of copper
in patients with mild to moderate Alzheimer’s disease. Journal of Alzheimer’s
Disease 8, 23–27.
Pan, Y., Loo, G., 2000. Effect of copper deficiency on oxidative DNA damage in Jurkat
T-lymphocytes. Free Radical Biology and Medicine 28, 824–830.
Paolisso, G., Barbieri, M., Bonafe, M., Franceschi, C., 2000. Metabolic age modelling:
the lesson from centenarians. European Journal of Clinical Investigation 30,
888–894.
Papadopoulou, L.C., Sue, C.M., Davidson, M.M., Tanji, K., Nishino, I., Sadlock, J.E.,
Krishna, S., Walker, W., Selby, J., Glerum, D.M., Coster, R.V., Lyon, G., Scalais, E.,
Lebel, R., Kaplan, P., Shanske, S., De Vivo, D.C., Bonilla, E., Hirano, M., DiMauro, S.,
Schon, E.A., 1999. Fatal infantile cardioencephalomyopathy with COX deficien-
cy and mutations in SCO2: a COX assembly gene. Nature Genetics 23, 333–337.
Papp, L.V., Lu, J., Holmgren, A., Khanna, K.K., 2007. From selenium to selenoproteins:
synthesis, identity, and their role in human health. Antioxidants and Redox
Signaling 9, 775–806.
Pearson, R., Fleetwood, J., Eaton, S., Crossley, M., Bao, S., 2008. Kruppel-like tran-
scription factors: a functional family. The International Journal of Biochemistry
and Cell Biology 40, 1996–2001.
Pena, M.M., Puig, S., Thiele, D.J., 2000. Characterization of the Saccharomyces
cerevisiae high affinity copper transporter Ctr3. The Journal of Biological
Chemistry 275, 33244–33251.
Pence, B.C., Buddingh, F., 1985. Effect of dietary selenium deficiency on incidence
and size of 1,2-dimethylhydrazine-induced colon tumors in rats. The Journal of
Nutrition 115, 1196–1202.
Peretz, A., Neve, J., Desmedt, J., Duchateau, J., Dramaix, M., Famaey, J.P., 1991.
Lymphocyte response is enhanced by supplementation of elderly subjects with
selenium-enriched yeast. The American Journal of Clinical Nutrition 53, 1323–
1328.
Peters, U., Chatterjee, N., Hayes, R.B., Schoen, R.E., Wang, Y., Chanock, S.J., Foster,
C.B., 2008. Variation in the selenoenzyme genes and risk of advanced distal
colorectal adenoma. Cancer Epidemiology, Biomarkers and Prevention 17,
1144–1154.
Petris, M.J., Mercer, J.F., Culvenor, J.G., Lockhart, P., Gleeson, P.A., Camakaris, J., 1996.
Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump
from the Golgi apparatus to the plasma membrane: a novel mechanism of
regulated trafficking. The EMBO Journal 15, 6084–6095.
Phinney, A.L., Drisaldi, B., Schmidt, S.D., Lugowski, S., Coronado, V., Liang, Y., Horne,
P., Yang, J., Sekoulidis, J., Coomaraswamy, J., Chishti, M.A., Cox, D.W., Mathews,
P.M., Nixon, R.A., Carlson, G.A., St George-Hyslop, P., Westaway, D., 2003. In vivo
reduction of amyloid-beta by a mutant copper transporter. Proceedings of the
National Academy of Sciences of the United States of America 100, 14193–
14198.
Powell, S.R., 2000. The antioxidant properties of zinc. The Journal of Nutrition 130,
1447S–1454S.
Prasad, A.S., 2000. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. The
Journal of Infectious Diseases 182 (Suppl 1) S62–S68.
Prasad, A.S., 2008. Zinc in human health: effect of zinc on immune cells. Molecular
Medicine 14, 353–377.
Prasad, A.S., 2012. Discovery of human zinc deficiency: 50 years later. Journal of
Trace Elements in Medicine and Biology 26, 66–69.
Prasad, A.S., Meftah, S., Abdallah, J., Kaplan, J., Brewer, G.J., Bach, J.F., Dardenne, M.,
1988. Serum thymulin in human zinc deficiency. The Journal of Clinical Inves-
tigation 82, 1202–1210.
Prasad, A.S., Beck, F.W., Bao, B., Fitzgerald, J.T., Snell, D.C., Steinberg, J.D., Cardozo,
L.J., 2007. Zinc supplementation decreases incidence of infections in the elderly:
effect of zinc on generation of cytokines and oxidative stress. The American
Journal of Clinical Nutrition 85, 837–844.
Prohaska, J.R., Gybina, A.A., 2004. Intracellular copper transport in mammals. The
Journal of Nutrition 134, 1003–1006.
G Model
MAD-10703; No. of Pages 21
20 E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx
Puig, S., Thiele, D.J., 2002. Molecular mechanisms of copper uptake and distribution.
Current Opinion in Chemical Biology 6, 171–180.
Quinn, J.F., Crane, S., Harris, C., Wadsworth, T.L., 2009. Copper in Alzheimer’s
disease: too much or too little? Expert Review of Neurotherapeutics 9, 631–
637.
Raaschou-Nielsen, O., Sorensen, M., Hansen, R.D., Frederiksen, K., Tjonneland, A.,
Overvad, K., Vogel, U., 2007. GPX1 Pro198Leu polymorphism, interactions with
smoking and alcohol consumption, and risk for lung cancer. Cancer Letters 247,
293–300.
Ratnasinghe, D., Tangrea, J.A., Andersen, M.R., Barrett, M.J., Virtamo, J., Taylor, P.R.,
Albanes, D., 2000. Glutathione peroxidase codon 198 polymorphism variant
increases lung cancer risk. Cancer Research 60, 6381–6383.
Ravaglia, G., Forti, P., Maioli, F., Bastagli, L., Facchini, A., Mariani, E., Savarino, L., Sassi,
S., Cucinotta, D., Lenaz, G., 2000. Effect of micronutrient status on natural killer
cell immune function in healthy free-living subjects aged > = 90 y. The Ameri-
can Journal of Clinical Nutrition 71, 590–598.
Ray, A.L., Semba, R.D., Walston, J., Ferrucci, L., Cappola, A.R., Ricks, M.O., Xue, Q.L.,
Fried, L.P., 2006. Low serum selenium and total carotenoids predict mortality
among older women living in the community: the women’s health and aging
studies. The Journal of Nutrition 136, 172–176.
Rayman, M.P., 2012. Selenium and human health. Lancet 379, 1256–1268.
Reid, M.E., Duffield-Lillico, A.J., Garland, L., Turnbull, B.W., Clark, L.C., Marshall, J.R.,
2002. Selenium supplementation and lung cancer incidence: an update of the
nutritional prevention of cancer trial. Cancer Epidemiology. Biomarkers and
Prevention 11, 1285–1291.
Reid, M.E., Duffield-Lillico, A.J., Sunga, A., Fakih, M., Alberts, D.S., Marshall, J.R., 2006.
Selenium supplementation and colorectal adenomas: an analysis of the nutri-
tional prevention of cancer trial. International Journal of Cancer 118, 1777–
1781.
Ridge, P.G., Zhang, Y., Gladyshev, V.N., 2008. Comparative genomic analyses of
copper transporters and cuproproteomes reveal evolutionary dynamics of
copper utilization and its link to oxygen. PLoS ONE 3, e1378–e1391.
Rink, L., Kirchner, H., 2000. Zinc-altered immune function and cytokine production.
The Journal of Nutrition 130, 1407S–1411S.
Ritchie, C.W., Bush, A.I., Mackinnon, A., Macfarlane, S., Mastwyk, M., MacGregor, L.,
Kiers, L., Cherny, R., Li, Q.X., Tammer, A., Carrington, D., Mavros, C., Volitakis, I.,
Xilinas, M., Ames, D., Davis, S., Beyreuther, K., Tanzi, R.E., Masters, C.L., 2003.
Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting
Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2
clinical trial. Archives in Neurology 60, 1685–1691.
Ross, R., 1999. Atherosclerosis is an inflammatory disease. American Heart Journal
138, S419–S420.
Ryan-Harshman, M., Aldoori, W., 2005. The relevance of selenium to immunity,
cancer, and infectious/inflammatory diseases. Canadian Journal of Dietetic
Practice and Research 66, 98–102.
Saba, I., Kosan, C., Vassen, L., Moroy, T., 2011. IL-7R-dependent survival and
differentiation of early T-lineage progenitors is regulated by the BTB/POZ
domain transcription factor Miz-1. Blood 117, 3370–3381.
Sahyoun, N.R., Jacques, P.F., Dallal, G., Russell, R.M., 1996. Use of albumin as a
predictor of mortality in community dwelling and institutionalized elderly
populations. Journal of Clinical Epidemiology 49, 981–988.
Saltman, P.D., Strause, L.G., 1993. The role of trace minerals in osteoporosis. Journal
of the American College of Nutrition 12, 384–389.
Sandstead, H.H., 1995. Requirements and toxicity of essential trace elements,
illustrated by zinc and copper. The American Journal of Clinical Nutrition 61
(3 (Suppl)) 621S–624S.
Sanz-Medel, A., Montes-Bayon, M., Luisa Fernandez Sanchez, M., 2003. Trace
element speciation by ICP-MS in large biomolecules and its potential for
proteomics. Analytical and Bioanalytical Chemistry 377, 236–247.
Savarino, L., Granchi, D., Ciapetti, G., Cenni, E., Ravaglia, G., Forti, P., Maioli, F.,
Mattioli, R., 2001. Serum concentrations of zinc and selenium in elderly people:
results in healthy nonagenarians/centenarians. Experimental Gerontology 36,
327–339.
Schomburg, L., Schweizer, U., Holtmann, B., Flohe, L., Sendtner, M., Kohrle, J., 2003.
Gene disruption discloses role of selenoprotein P in selenium delivery to target
tissues. The Biochemical Journal 370, 397–402.
Schwarz, S., 1976. Essentiality and metabolic functions of selenium. The Medical
Clinics of North America 60, 745–758.
Seiler, W.O., 2001. Clinical pictures of malnutrition in ill elderly subjects. Nutrition
17, 496–498.
Seiler, A., Schneider, M., Forster, H., Roth, S., Wirth, E.K., Culmsee, C., Plesnila, N.,
Kremmer, E., Radmark, O., Wurst, W., Bornkamm, G.W., Schweizer, U., Conrad,
M., 2008. Glutathione peroxidase 4 senses and translates oxidative stress into
12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metabolism
8, 237–248.
Semba, R.D., Blaum, C.S., Bartali, B., Xue, Q.L., Ricks, M.O., Guralnik, J.M., Fried, L.P.,
2006. Denture use, malnutrition, frailty, and mortality among older women living
in the community. The Journal of Nutrition, Health and Aging 10, 161–167.
Sensi, S.L., Jeng, J.M., 2004. Rethinking the excitotoxic ionic milieu: the emerging
role of Zn(2+) in ischemic neuronal injury. Current Molecular Medicine 4, 87–
111.
Sharif, R., Thomas, P., Zalewski, P., Fenech, M., 2012a. The role of zinc in genomic
stability. Mutation Research 733, 111–121.
Sharif, R., Thomas, P., Zalewski, P., Fenech, M., 2012b. Zinc deficiency or excess
within the physiological range increases genome instability and cytotoxicity,
respectively, in human oral keratinocyte cells. Genes and Nutrition 7, 139–154.
Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007
Shibata, T., Arisawa, T., Tahara, T., Ohkubo, M., Yoshioka, D., Maruyama, N., Fujita, H.,
Kamiya, Y., Nakamura, M., Nagasaka, M., Iwata, M., Takahama, K., Watanabe, M.,
Hirata, I., 2009. Selenoprotein S (SEPS1) gene 105G > A promoter polymor-
phism influences the susceptibility to gastric cancer in the Japanese population.
BMC Gastroenterology 9, 230–239.
Shukla, N., Maher, J., Masters, J., Angelini, G.D., Jeremy, J.Y., 2006. Does oxidative
stress change ceruloplasmin from a protective to a vasculopathic factor?
Atherosclerosis 187, 238–250.
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D.,
Belisle, A., Hadjadj, S., Balkau, B., Heude, B., Charpentier, G., Hudson, T.J.,
Montpetit, A., Pshezhetsky, A.V., Prentki, M., Posner, B.I., Balding, D.J., Meyre,
D., Polychronakos, C., Froguel, P., 2007. A genome-wide association study
identifies novel risk loci for type 2 diabetes. Nature 445, 881–885.
Spahl, D.U., Berendji-Grun, D., Suschek, C.V., Kolb-Bachofen, V., Kroncke, K.D., 2003.
Regulation of zinc homeostasis by inducible NO synthase-derived NO: nuclear
metallothionein translocation and intranuclear Zn2+ release. Proceedings of the
National Academy of Sciences of the United States of America 100, 13952–
13957.
Sparks, D.L., 2004. Cholesterol, copper, and accumulation of thioflavine S-reactive
Alzheimer’s-like amyloid beta in rabbit brain. Journal of Molecular Neurosci-
ence 24, 97–104.
Spencer, N.F., Poynter, M.E., Im, S.Y., Daynes, R.A., 1997. Constitutive activation of
NF-kappa B in an animal model of aging. International Immunology 9, 1581–
1588.
Squitti, R., Rossini, P.M., Cassetta, E., Moffa, F., Pasqualetti, P., Cortesi, M., Colloca, A.,
Rossi, L., Finazzi-Agro, A., 2002. d-Penicillamine reduces serum oxidative stress
in Alzheimer’s disease patients. European Journal of Clinical Investigation 32,
51–59.
Stadler, N., Lindner, R.A., Davies, M.J., 2004. Direct detection and quantification of
transition metal ions in human atherosclerotic plaques: evidence for the
presence of elevated levels of iron and copper. Arteriosclerosis, Thrombosis,
and Vascular Biology 24, 949–954.
Steveson, T.C., Ciccotosto, G.D., Ma, X.M., Mueller, G.P., Mains, R.E., Eipper, B.A.,
2003. Menkes protein contributes to the function of peptidylglycine alpha-
amidating monooxygenase. Endocrinology 144, 188–200.
Stover, P.J., 2006. Influence of human genetic variation on nutritional requirements.
The American Journal of Clinical Nutrition 83, 436S–442S.
Stranges, S., Marshall, J.R., Natarajan, R., Donahue, R.P., Trevisan, M., Combs, G.F.,
Cappuccio, F.P., Ceriello, A., Reid, M.E., 2007. Effects of long-term selenium
supplementation on the incidence of type 2 diabetes: a randomized trial. Annals
of Internal Medicine 147, 217–223.
Suzuki, K.T., Someya, A., Komada, Y., Ogra, Y., 2002. Roles of metallothionein in
copper homeostasis: responses to Cu-deficient diets in mice. Journal of Inor-
ganic Biochemistry 88, 173–182.
Swamynathan, S.K., 2010. Kruppel-like factors: three fingers in control. Human
Genomics 4, 263–270.
Tang, N.P., Wang, L.S., Yang, L., Gu, H.J., Sun, Q.M., Cong, R.H., Zhou, B., Zhu, H.J.,
Wang, B., 2008. Genetic variant in glutathione peroxidase 1 gene is associated
with an increased risk of coronary artery disease in a Chinese population.
Clinica Chimica Acta 395, 89–93.
Tapia, L., Gonzalez-Aguero, M., Cisternas, M.F., Suazo, M., Cambiazo, V., Uauy, R.,
Gonzalez, M., 2004. Metallothionein is crucial for safe intracellular copper
storage and cell survival at normal and supra-physiological exposure levels.
The Biochemical Journal 378, 617–624.
Toniato, E., Chen, X.P., Losman, J., Flati, V., Donahue, L., Rothman, P., 2002. TRIM8/
GERP RING finger protein interacts with SOCS-1. The Journal of Biological
Chemistry 277, 37315–37322.
Tsaih, S.W., Pezzolesi, M.G., Yuan, R., Warram, J.H., Krolewski, A.S., Korstanje, R.,
2010. Genetic analysis of albuminuria in aging mice and concordance with loci
for human diabetic nephropathy found in a genome-wide association scan.
Kidney International 77, 201–210.
Turnlund, J.R., Keyes, W.R., Kim, S.K., Domek, J.M., 2005. Long-term high copper
intake: effects on copper absorption, retention, and homeostasis in men. The
American Journal of Clinical Nutrition 81, 822–828.
Uciechowski, P., Kahmann, L., Plumakers, B., Malavolta, M., Mocchegiani, E., Dedous-
sis, G., Herbein, G., Jajte, J., Fulop, T., Rink, L., 2008. TH1 and TH2 cell polarization
increases with aging and is modulated by zinc supplementation. Experimental
Gerontology 43, 493–498.
Ugarte, M., Osborne, N.N., 2001. Zinc in the retina. Progress in Neurobiology 64,
219–249.
Underwood, E.J., 1981. Trace metals in human and animal health. Journal of Human
Nutrition 35, 37–48.
Vallee, B.L., 1995. The function of metallothionein. Neurochemistry International
27, 23–33.
Ventura, M.T., Serlenga, E., Tortorella, C., Antonaci, S., 1994. In vitro vitamin E and
selenium supplementation improves neutrophil-mediated functions and
monocyte chemoattractant protein-1 production in the elderly. Cytobios 77,
225–232.
Vinceti, M., Solovyev, N., Mandrioli, J., Crespi, C.M., Bonvicini, F., Arcolin, E., Geor-
goulopoulou, E., Michalke, B., 2013. Cerebrospinal fluid of newly diagnosed
amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium
species including elevated selenite. Neurotoxicology 38, 25–32.
Visser, M., Kritchevsky, S.B., Newman, A.B., Goodpaster, B.H., Tylavsky, F.A., Nevitt,
M.C., Harris, T.B., 2005. Lower serum albumin concentration and change in
muscle mass: the health, aging and body composition study. The American
Journal of Clinical Nutrition 82, 531–537.
G Model
MAD-10703; No. of Pages 21

E. Mocchegiani et al. / Mechanisms of Ageing and Development xxx (2014) xxx–xxx 21

Voetsch, B., Jin, R.C., Bierl, C., Benke, K.S., Kenet, G., Simioni, P., Ottaviano, F.,
Damasceno, B.P., Annichino-Bizacchi, J.M., Handy, D.E., Loscalzo, J., 2007. Pro-
moter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a
novel risk factor for arterial ischemic stroke among young adults and children.
Stroke 38, 41–49.
Walston, J., Xue, Q., Semba, R.D., Ferrucci, L., Cappola, A.R., Ricks, M., Guralnik, J.,
Fried, L.P., 2006. Serum antioxidants, inflammation, and total mortality in older
women. American Journal of Epidemiology 163, 18–26.
Wang, P., Guliaev, A.B., Hang, B., 2006. Metal inhibition of human N-methylpurine-
DNA glycosylase activity in base excision repair. Toxicology Letters 166, 237–
247.
Weiss, J.H., Sensi, S.L., Koh, J.Y., 2000. Zn(2+): a novel ionic mediator of neural injury
in brain disease. Trends in Pharmacological Sciences 21, 395–401.
Wellinghausen, N., Martin, M., Rink, L., 1997. Zinc inhibits interleukin-1-dependent
T cell stimulation. European Journal of Immunology 27, 2529–2535.
West, A.K., Stallings, R., Hildebrand, C.E., Chiu, R., Karin, M., Richards, R.I., 1990.
Human metallothionein genes: structure of the functional locus at 16q13.
Genomics 8, 513–518.
Windler, E., Schoffauer, M., Zyriax, B.C., 2007. The significance of low HDL-choles-
terol levels in an ageing society at increased risk for cardiovascular disease.
Diabetes and Vascular Disease Research 4, 136–142.
Wong, C.P., Ho, E., 2012. Zinc and its role in age-related inflammation and immune
dysfunction. Molecular Nutrition and Food Research 56, 77–87.
Wood, S.M., Beckham1, C., Yosioka2, A., Darban3, H., Watson, R.R., 2000. beta-
Carotene and selenium supplementation enhances immune response in aged
humans. Integrative Medicine 2, 85–92.
Yang, S.W., Becker, F.F., Chan, J.Y., 1996. Inhibition of human DNA ligase I activity by
zinc and cadmium and the fidelity of ligation. Environmental and Molecular
Mutagenesis 28, 19–25.
Yang, K.C., Lee, L.T., Lee, Y.S., Huang, H.Y., Chen, C.Y., Huang, K.C., 2010. Serum
selenium concentration is associated with metabolic factors in the elderly: a
cross-sectional study. Nutrition and Metabolism 7 , 38-707-5-47.
Yetkin, E., Waltenberger, J., 2009. Molecular and cellular mechanisms of aortic
stenosis. International Journal of Cardiology 135, 4–13.
Zarbin, M.A., 2004. Current concepts in the pathogenesis of age-related macular
degeneration. Archives of Ophthalmology 122, 598–614.

Please cite this article in press as: Mocchegiani, E., et al., Micronutrient–gene interactions related to inflammatory/immune response
and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev. (2014), http://dx.doi.org/10.1016/
j.mad.2013.12.007