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reactions [ 94 ]. These antioxidant factors are supplied to the human system either by
endogenous process or through the dietary sources. Endogenously, the activation of
several signaling proteins and transcription factors such as NFκB, AP1, HIF1α, p53
and Nrf2 (nuclear factor (erythroid-derived 2)-like 2) exerts transcriptional control
of antioxidant signaling by regulating the expression of genes that encode antioxi-
dant enzymes, phase-2 enzymes, protein chaperones, and other cytoprotective
machinery [ 95 , 96 ]. Although antioxidants protect the system from the attack of
oxidative stress and associated damage, the hypothesis that organismal lifespan can
be enhanced by increasing antioxidant defenses is still vague due to conflicting
results in certain aging models. For instance, studies in mammals in which levels of
endogenous antioxidant genes are experimentally increased have shown that maxi-
mum longevity either is minimally increased or not affected [ 43 , 97 , 98 ]. In fact,
double transgenic mice overexpressing both CuZnSOD and catalase did not show
a significant change in the lifespan [ 43 ]. These lifespan studies understandably used
the survival of the organism as their endpoint measurement and the possibility that
overexpression of these antioxidant genes in slowing down the rate of aging of indi-
vidual organs are not focused. At this juncture, it is to be considered that certain
intrinsic changes always co-occur with age, however, all organs need not age alike
and a specific organ can show signs of aging phenotypes before the other. Particularly,
organism and organ age need not always proceed concomitantly [ 99 – 101 ].
Especially, this can be true in the case of heart as this is a nonstop working organ
with remarkable plasticity besides facing a continuous challenge to its organ reserve,
an ability to adjust and function beyond the typical needs. A recent large-scale study
revealed that how cellular proteins (that determines the function) age differently in
different niches indicating that the cellular property and the physiology of a specific
organ can drive its course of aging [ 102 ]. Thus, the amplitude of response can vary
depending on the severity of oxidant/antioxidant imbalance, inherent tolerance to
alterations, cellular context and physiology of the specific organ and several other
regulatory factors resulting in either adaptation/advantage (Eustress), stress and/or
unresolved stress (Distress or Destruction) [ 103 ] (Fig. 13.2).
It is widely agreed that with age there is an apparent decline in the productionand activity of biological antioxidants resulting in an overburden of ROS/RNS [ 56 ].
A component of the cellular antioxidant and detoxification pathway is the battery of
genes bearing the antioxidant response element (AREs) such as NAD(P)H-quinone
oxidase-1 (NQO1), heme oxygenase (HO1), ϓ-glutamyl cysteine ligase-catalytic
(GCLC), ϓ-glutamyl ligase-modulatory (GCLM), glucose-6-phosphate
dehydrogenase (G6PD), glutathione peroxidase-1 (GPX1), glutathione peroxi-
dase-2 (GPX2), glutathione reductase (GSR), catalase (CAT) to scavenge the
endogenous reactive intermediates and toxin export genes (multidrug response
transporter family, MDR) [ 96 , 104 , 105 ], all of which are regulated by nuclear fac-
tor erythroid-2-p45-related factor-2 (Nrf2). It is originally discovered as a Cap ‘n’
Collar (CNC) family of basic leucine zipper (bZip)-DNA binding protein that can
bind to erythroid transcription factor 2 (NF-E2) binding motif [ 106 ]. Later it has
been established as a major transcription factor that heterodimerizes with small
musculoaponeurotic fibrosarcoma (Maf) proteins and drives the expression of
M. Narasimhan and N.-S. Rajasekaran