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This free radical theory of aging has become the mitochondrial free radical theory of aging, which is the most famous version of Harman’s theory. Sixteen years later, Harman himself concluded that mitochondria are both the source and target of free radicals. The “free radical theory of aging”, published more than 50 years ago by Harman, states that the generation and accumulation of free radicals with aging results in oxidative damage to critical biological molecules such as DNA, proteins, and lipids ( Figure 1).
OH is the most reactive species, and interacts with the C-8 position of guanine to form 8-hydroxyguanine, which is one of the most commonly found oxidized bases in DNA. Free radicals are deleterious in many ways, such as by damaging nucleobases or sugar units. As a consequence of DNA being constantly attacked by free radicals, approximately 75,000–100,000 DNA damage events might occur in each cell per day. ROS react with nucleic acids, proteins, and membrane lipids largely in a nonspecific manner, which may result in gene mutations, impairments or loss of enzyme activity, or altered cell membrane permeability, whereas RNS directly or indirectly lead to protein S-nitrosylation. Apart for beneficial effects, free radical causes lot of deleterious effects. These enzymes are highly active in the reproductive system, and ROS are involved in variety of functions, including elevation of intracellular Ca 2+ concentrations, phosphorylation of specific proteins, activation of specific transcription factors, modulation of eicosanoid metabolism, stimulation of cell growth, and physiological mediators of control for several transcription factors. Superoxide radical and NO are the most commonly synthesized reactive species produced by NADPH oxidases and NO synthases, respectively. Free radicals such as ROS and RNS arise as intermediates in many metabolic processes, are generated specifically as part of a cellular defense mechanism against invaded pathogens, and regulate several processes including glucose metabolism, cellular growth, and proliferation. Besides ROS, reactive nitrogen species (RNS), including nitric oxide (NO), peroxynitrite (NO 3 −), S-nitrosothiols also contribute to the generation of free radicals. Major ROS include superoxide anion (O 2 −), hydrogen peroxide (H 2O 2), and hydroxyl radical ( In biological systems, the term free radicals mostly refers to reactive oxygen species (ROS) and are oxygen centered. 
Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.Ĭhemical species with unpaired or an odd number of electrons are called free radicals. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron.
Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Dopaminergic neurons show linear fallout of 5–10% per decade with aging however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD).
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