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Anti-Aging properties of superoxid dismutase
Superoxide dismutase (SOD) is an antioxidant enzyme that protects tissues and cells of the body from damage due to oxidation reactions. It catalyzes the dismutation of the superoxide radical into hydrogen peroxide and molecular oxygen and plays a pivotal role in protecting tissues from oxidative stress [1].
There are different forms of the enzyme depending on the catalytically active metal which may be copper, iron, manganese or nickel [2]. The most significant form in humans is the Mn-SOD form present in the mitochondria, with manganese at its active site. Mn-SOD acts as the paramount ROS scavenging enzyme in the cell, thus preventing the dramatic effects of aberrant mitochondrial ROS on cellular function. Factors that affect the activity of MnSOD can lead to substantial consequences on the overall health of the cell by the alteration of mitochondrial metabolic function, resulting in the development and progression of numerous diseases [3]. The action of this enzyme to eliminate superoxide radicals involves the sequential reduction and oxidation of the metal center, with the concomitant oxidation and reduction of superoxide radicals into molecular oxygen and hydrogen peroxide [4].
Various studies suggest that an imbalance between free radicals and antioxidants can lead to accelerated aging [5]. A number of studies have been conducted to link SOD and its mimetics/ analogs like Tempo, Tempol, EUK-8, EUK-134, and MnTBAP, with longevity and aging. Some of these studies have shown that a decrease in SOD levels is associated with various age-related conditions and faster aging. One study in mice demonstrated that the lack of SOD in connective tissues resulted in reduced lifespan and premature onset of aging-related characteristics like weight loss, skin atrophy, kyphosis, osteoporosis and muscle degeneration [6]. A second study generated Mn-superoxide deficient mice and observed that they developed progressive dilated cardiomyopathy and severe physical disturbances linked to impaired cellular ATP metabolism in skeletal muscles, conditions commonly found in older populations [7]. A third study showed that mice with genetic overexpression of EC-SOD do not show the aging-induced decline in learning and memory that wild type mice show, concluding that novel EC-SOD analogues may be useful in attenuating aging-induced cognitive impairments and other aspects of physiological decline with aging [8]. Another study utilized C. elegans, a worm for testing longevity, by augmenting the natural antioxidant systems of the test organism with SOD mimetics. Results showed that the life span of wild-type worms increased by 44 percent, and treatment of prematurely aging worms resulted in normalization of life-span (a 67 % increase) [9].
In spite of these results, other studies show conflicting outcomes. One study generated mice with a combined deficiency of both Mn-superoxide dismutase (Mn-SOD) and glutathione peroxidase-1. Surprisingly, the mice showed no reduction in life span, despite increased levels of oxidative damage, pathologies and increased incidence of neoplasms[10]. Another study on C. elegans utilized EUK-8 and EUK-134, synthetic mimetics of SOD, and showed elevated SOD activity levels in all test organisms; however, only those groups whose life span was reduced by superoxide generators paraquat and plumbagin showed a dose-dependent increased life span. In the absence of a superoxide generator, EUK-8 and EUK-134 did not increase life span, even at optimal doses [11]. A seventh study proposed that SOD overexpression increases C. elegans life span, not by removal of free radicals, but instead by activating longevity-promoting transcription factors [12].
In a study using human subjects, SOD leukocyte induction was performed using paraquat. Forty healthy subjects were followed up 5 years later. All subjects who had died had shown SOD induction of less than 10%, while in the 21 survivors, 12 had shown SOD induction greater than 10%, and 7 had shown SOD induction greater than or equal to 35%. The study suggested that leukocyte SOD inducibility appears to correlate with longevity in elderly individuals [13].
Numerous years of research between SOD activity and aging or life span have not yet come up with a consistent picture of its role in aging [14]. With conflicting results in the literature, a meta-analysis linking SOD to longevity has yet to be published; however, it is believed that the mechanisms of aging and longevity depend on multiple factors [15] and there is still much room for advanced research.
REFERENCES:
1. Chaudhary N, Chand S, & Kaur N. (2013). Studies on Biochemical Characteristics of Thermostable Superoxide Dismutase isolated from Ribes nigrum: A Functional Food. Biotech 2013: 49-53.
2. Characterization of iron superoxide dismutase cDNAs from plants obtained by genetic complementation in Escherichia coli. Proc Natl Acad Sci USA 87 (24): 9903-9907.
3. Holley AK, Bakthavatchalu V, Velez-Roman JM & St Clair DK. (2011). Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci 12 (10): 7114-7162.
4. Abreu IA & Cabelli DE. (2010). Superoxide dismutases—a review of the metal-associated mechanistic variations. Biochim Biophys Acta 1804 (2): 263-274.
5. Goldberg LD & Crysler, C. (2014). A single center, pilot, double-blinded, randomized, comparative, prospective clinical study to evaluate improvements in the structure and function of facial skin with tazarotene 0.1% cream alone and in combination with GliSODin Skin Nutrients. Clin Cosmet Investig Dermatol 7: 139-144.
6. Treiber N, Maity P, Singh K, Kohn M, Keist AF & Ferchiu, F. (Apr 2011). Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue. Aging Cell 10 (2): 239-254.
7. Shimizu T & Shirasawa T. (2010). Anti-aging research using Mn-SOD conditional knockout mice. Yakugaku Zasshi, 130 (1): 19-24.
8. Levin, E. (2005). Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: opportunities for novel drug development in aging. Curr Alzheimer Res 2 (2): 191-196.
9. Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow, SR, & Lithgow GJ. (2000). Science 289 (5484): 1567-1569.
10. Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y, Bokov A, Thorpe SR, Baynes JW, Epstein C, Richardson A, Van Remmen H. (2009). Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J Gerontol A Biol Sci Med Sci 64A (12): 1212-1220.
11. Keaney M, Matthijssens F, Sharpe M, Vanfleteren J, & Gems D. (2004). Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but do not retard aging in the nematode Caenorhabditis elegans. Free Radic Biol Med 17 (3): 249-258.
12. Cabreiro F, Ackerman D, Doonan R, Araiz C, Back P, Papp D, Braeckman BP & Gems D. (2011). Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med 51 (8): 1575-82.
13. Niwa Y, Ishimoto K &Kanoh T. (1990). Induction of superoxide dismutase in leukocytes by paraquat: correlation with age and possible predictor of longevity. Blood 76 (4): 835-841.
14. Warner HR. (1994). Superoxide dismutase, aging, and degenerative disease. Free Radic Biol Med 17 (3): 249-258.
15. Yong-Xing M, Zan-Sun W, Yue Z, Shu-Ying C, Zheng-Yan Y, Long Q, Jian-Ying Y, Shu-Qi C, Jian-Gang Z & Lin H. (1998) Mech Ageing Dev 100 (2): 187-196.
