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cardiomyocytes can make the myocardium more susceptible to stress, aging,
diseases and other toxic insults [ 123 – 125 ]. A mild to moderate increase in ROS
level is shown to activate Nrf2 and subsequent antioxidant and detoxification
mechanisms in the vasculature of young animals as an adaptive response [ 64 ,
126 ]. In contrast, under circumstances of strong oxidation as in a 5-month
chronic hyperglycemia mice model, Nrf2 and its response in the heart is found
to be severely dampened compared to a 2-month old hyperglycemic model that
can represent a modest redox perturbation [ 127 ]. Notably, nuclear Nrf2 levels
were significantly decreased in the autopsied heart specimens from diabetic
patients compared to control hearts [ 127 ]. This indicates that the intracellular
level of ROS in the heart, i.e. low to mild representing physiological and strong
to the persistent representing pathological scenario can bi-modally regulate
Nrf2 thus making it as an attractive candidate for further studies.
Previous reports suggest that aged mice display a similar reduction in cellularredox capacity as that of Nrf2 knockout mice [ 118 , 128 ]. In contrast, augmented
activity of Nrf2 and ARE-responsive genes has been observed in long-lived rodents
such as naked mole rats and Snell Dwarf mice [ 129 – 131 ]. Interestingly a classical
study that compared eight rodent species with vastly differing longevities ranging
from 4 to 31 years observed a strong correlation between Nrf2-ARE binding activ-
ity and maximum lifespan potential [ 130 ]. The role of Nrf2 in aging and human
disease is extensively reviewed elsewhere [ 132 ]. Several mechanistic studies have
elaborately demonstrated that age-related deficiency and/or insufficient activity of
Nrf2 impairs cell’s ability to mount an adaptive response and detoxify the oxygen
radicals affecting the redox homeostasis leading to OS and/or oxidant sensitivity in
the myocardium and heart failure [ 56 , 69 , 126 , 133 , 134 ]. Moreover, disturbances in
redox homeostasis are reported to induce apoptosis and/or necrosis of myocyte
resulting in decreased myocyte number, a hallmark of aging heart that in turn,
results in remodeling and hypertrophy [ 66 ]. Thus, an increase in ROS concentration
that can stem from a combination of two intrinsic sources namely aging and myo-
cardium, an organ that is rich in mitochondria which are a seat of oxidative metabo-
lism has the high likelihood of weakening the heart-directed stress responses in the
elderly even in the absence of any pathology. While, in the presence of any pathol-
ogy, the ability of the cells to respond and restore from toxic challenges could be
greatly debilitated. In this connection, such a mechanism involving Nrf2 to control
the oxidative burden in the aging heart can be highly relevant. Of note, these lines
of evidence and thoughts clearly point out that Nrf2 pathway is at the intersection of
both aging and cardiac physiology wherein, a decline in Nrf2-antioxidant signaling
during aging can predispose the cardiac tissues to various adverse etiologies of dis-
ease development [ 56 , 67 ]. Taking these facts into account, Nrf2 may be regarded
as a “gatekeeper of cardiac longevity and myocardial health”.
More complex, yet interesting is the fact that in physically fit who undergoesprogressive training, there is a decreased incidence of OS based pathologies. This is
due to the reinforcement of adaptive resistance to OS along with induction of tro-
phic factors and activation of oxidative-damage repairing systems [ 135 – 140 ].
Hence, in the next section we will discuss the systematic functions (up and down
M. Narasimhan and N.-S. Rajasekaran