Abstract
The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD∶NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I–IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.
Highlights
Multiple degenerative processes are implicated in natural senescence
This study is the first to investigate the impact of age associated changes in oxidative stress levels on both intracellular NAD+ levels and activity of the ‘longevity’ enzyme Sirt1
While oxidative stress increases with aging, it is yet unclear at which age free-radicals may act to initiate the senescence process
Summary
Multiple degenerative processes are implicated in natural senescence. As aging is associated with progressive decline in organ function, elucidating the complex pathways controlling the rate of aging is of significant clinical importance [1]. An important mechanism contributing to aging is oxidative stress. The ‘‘freeradical theory of aging’’, initially proposed by Harman (1956) suggests that oxidative damage occurs with advanced aging due to an imbalance between free radical and reactive species (ROS) production, and cellular antioxidant defense mechanisms [2]. Intracellular ROS, due to their high reactivity, can interact with a spectrum of biological molecules, leading to the oxidation of several macromolecules, such as protein, lipids, and nucleic acids [8]. Vital functions, such as energy production, maintenance of plasma membrane potential, and cellular ionic homeostasis may be impaired in the early stage of oxidative stress [8]. Excessive oxidative insult may stimulate secondary events leading to cell death via an apoptotic mechanism [9]
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