Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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signaling being a common denominator for aging and several cardiovascular dis-

eases such as heart failure, stroke, myocardial infarction (MI), cardiomyopathies,

hypertension, coronary heart disease etc. [ 29 – 32 ], in this chapter, we will discuss on

how cellular antioxidant signaling influence cardiac aging and its associated pheno-

type in the cardiovascular system in response to different types of exercise.

4 Relevance of Redox to Aging and Cardiac Health

Accumulation of evidence indicates that redox state of a cell and their responses to

stress plays a critical role in aging and cardiovascular health [ 29 , 30 , 32 ]. In fact,

redox signaling has a close relationship to the oldest free radical theory of aging

[ 33 ] as well as the recently reviewed genetic mutation theory, the wear and tear

theory, and the cellular waste accumulation theory [ 34 ]. Several clinical and pre-

clinical studies have shown an age-related oxidative shift in the thiol/disulfide redox

status, particularly in the ratio of reduced to oxidized glutathione, which is a major

cellular antioxidant [ 35 – 37 ]. Further, age-related oxidative stress can inactivate the

conformation, stability, molecular interactions, and activity of several signal trans-

ducers such as phosphatases, ion transporters, receptors, kinases that participate in

diverse processes namely gene transcription, proteasome inactivation, loss of repair

mechanisms etc., suggesting that there is an unavoidable alteration in the most, if

not all, of the physiological mechanisms and set points concerning the redox homeo-

stasis [ 38 – 40 ]. This can sustain the aging-oxidative stress cyclical process. At the

same time, it is also to be reminded that the oxyradicals or oxidants may not always

cause damage and perturb the aging process. In other words, the redox signaling

cannot be completely viewed as a mechanism similar to on-off switch (presence of

oxidants/absence of oxidants), rather it must be viewed as a specific and/or precise

balancing of the oxidation-reduction process and the levels of redox messengers

lying within the physiological range [ 41 ]. However, an ambiguity in the field still

exists as to whether or not redox stress plays an important role in the aging process

[ 42 , 43 ]. But, given the fact that oxygen is essential for life with an accrual and

increased rate of oxidative damage and its associated physiological impairments

with age, it is not surprising to believe that any exogenous or endogenous mecha-

nisms that alter the oxygen metabolism perturbing the redox homeostasis either

largely or continuously can derange the health maintenance processes and can

impact both the longevity as well as the quality of aging [ 44 – 46 ].

Effective heart function also chiefly depends on the oxidative energy production

which is evident from the fact that it consumes approximately 8–15  ml O 2 /

min/100  g tissue at resting state. While this can be increased to >70  ml O2/

min/100  g myocardial tissue during vigorous exercise [ 47 , 48 ]. In short, heart

exhibits high oxygen consumption. Further, the heart is composed of array of cell

types such as cardiomyocytes (essential for heart contraction contributes by gener-

ating and conduct electrical signals), fibroblasts (ensures proper cardiac form and

cell-cell communication), endothelial cells (functions in nutrient intake, oxygen

13 Cardiac Agingfi– Bene ts offiExercise, Nrf2 Activation andfiAntioxidant Signaling