Aging can be described as a complex progressive biological process that leads to physical and mental deterioration and eventually death [[1]Partridge L. Deelen J. Slagboom P.E. Facing up to the global challenges of ageing.Nature. 2018; 561: 45-56Crossref PubMed Scopus (438) Google Scholar]. It represents the accumulation of cellular and molecular alterations from environmental insults, genetics predispositions, and epigenetic responses [[2]Fearon I.M. Risk factors, oxidative stress, and cardiovascular disease.in: Laher I. Systems Biology of Free Radicals and Antioxidants. Springer Berlin Heidelberg, Berlin, Heidelberg2014: 765-790Crossref Scopus (2) Google Scholar] that occur over time. Cumulatively, these enhance the risk of a broad range of diseases, including thrombotic diseases, such as stroke, myocardial infarction, and venous thromboembolism [[3]Engbers M.J. van Hylckama Vlieg A. Rosendaal F.R. 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Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase.Nat Genet. 1995; 11: 376-381Crossref PubMed Scopus (1453) Google Scholar,[29]Lebovitz R.M. Zhang H. Vogel H. Cartwright Jr., J. Dionne L. Lu N. Huang S. Matzuk M.M. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice.Proc Natl Acad Sci U S A. 1996; 93: 9782-9787Crossref PubMed Scopus (838) Google Scholar]. Earlier studies have shown that lifelong SOD2 deficiency in aging mice results in higher atherosclerotic plaque formation, leading to increased vascular and cardiac dysfunction [[30]Vendrov A.E. Stevenson M.D. Alahari S. Pan H. Wickline S.A. Madamanchi N.R. Runge M.S. Attenuated superoxide dismutase 2 activity induces atherosclerotic plaque instability during aging in hyperlipidemic mice.J Am Heart Assoc. 2017; 6Crossref PubMed Scopus (35) Google Scholar,[31]Van Remmen H. Williams M.D. Guo Z. Estlack L. Yang H. Carlson E.J. Epstein C.J. Huang T.T. Richardson A. Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.Am J Physiol Heart Circ Physiol. 2001; 281: H1422-H1432Crossref PubMed Google Scholar]. Of note, these studies used heterozygous SOD2 knockout mice with 16-month-old mice categorized as middle-aged mice, equivalent to the 40- to 59-year age group in humans. Previous reports suggest that although deletion of SOD2 is deleterious to cells, its overexpression does not increase lifespan [[32]Jang Y.C. Perez V.I. Song W. Lustgarten M.S. Salmon A.B. Mele J. Qi W. Liu Y. Liang H. Chaudhuri A. Ikeno Y. Epstein C.J. Van Remmen H. Richardson A. Overexpression of Mn superoxide dismutase does not increase life span in mice.J Gerontol A Biol Sci Med Sci. 2009; 64: 1114-1125Crossref PubMed Scopus (152) Google Scholar]. The recent exciting study by Sonkar et al. [[33]Sonkar V.K. Eustes A.S. Ahmed A. Jensen M. Solanki M.V. Swamy J. Kumar R. Fidler T.P. Houtman J.C.D. Allen B.G. Spitz D.R. Abel E.D. Dayal S. Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging.Arterioscler Thromb Vasc Biol. 2023; 43: 79-91Crossref PubMed Scopus (3) Google Scholar] published in Arteriosclerosis, Thrombosis, and Vascular Biology provides further mechanistic insights into the crucial role of the SOD2 (MnSOD) in platelets with aging (summarized in Figure 1). Using young (4-5 months) and aged (18-20 months) wild-type and platelet-specific SOD2 knockout mice, the authors demonstrated that although the platelet SOD2 deletion in mice does not affect platelet aggregation and adhesion, SOD2 serves as a major regulator of mitochondrial function, ROS accumulation calcium regulation, thrombin generation, and arterial thrombosis during aging. The role of platelet SOD2 clearly becomes more relevant with age as an earlier study by Fidler et al. [[34]Fidler T.P. Rowley J.W. Araujo C. Boudreau L.H. 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Over the past few decades, identification of genetic polymorphisms, especially those associated with protein encoding genes, has opened new avenues in understanding the pathogenesis of human diseases and the nature of phenotypic diversity. Single-nucleotide polymorphisms of the human MnSOD gene have been observed in both the sequences coding for the mature protein and the sequences required for mitochondrial targeting [36Sutton A. Khoury H. Prip-Buus C. Cepanec C. Pessayre D. Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.Pharmacogenetics. 2003; 13: 145-157Crossref PubMed Scopus (360) Google Scholar, 37Xu Y. Fang F. Dhar S.K. St Clair W.H. Kasarskis E.J. St Clair D.K. The role of a single-stranded nucleotide loop in transcriptional regulation of the human sod2 gene.J Biol Chem. 2007; 282: 15981-15994Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 38Bonetta Valentino R. 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Association of Superoxide dismutases (SOD1 and SOD2) and Glutathione peroxidase 1 (GPx1) gene polymorphisms with type 2 diabetes mellitus.Free Radic Res. 2015; 49: 17-24Crossref PubMed Scopus (48) Google Scholar], coronary artery disease [[42]Souiden Y. Mallouli H. Meskhi S. Chaabouni Y. Rebai A. Cheour F. Mahdouani K. MnSOD and GPx1 polymorphism relationship with coronary heart disease risk and severity.Biol Res. 2016; 49: 22Crossref PubMed Scopus (34) Google Scholar], and cardiomyopathy [[43]Hiroi S. Harada H. Nishi H. Satoh M. Nagai R. Kimura A. Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese.Biochem Biophys Res Commun. 1999; 261: 332-339Crossref PubMed Scopus (167) Google Scholar]. Prevalence of these diseases increases substantially with age, and these diseases have also been closely linked to platelet hyperactivation and thrombosis [[44]Le Blanc J. Lordkipanidze M. Platelet function in aging.Front Cardiovasc Med. 2019; 6: 109Crossref PubMed Scopus (42) Google Scholar]. Previous studies show that missense mutations in SOD2 are especially prevalent in populations with African ancestry and are associated with a higher risk of vascular complications and age-mediated CVDs [[45]Stessman J. Maaravi Y. Hammerman-Rozenberg R. Cohen A. Nemanov L. Gritsenko I. Gruberman N. Ebstein R.P. Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study.Mech Ageing Dev. 2005; 126: 333-339Crossref PubMed Scopus (43) Google Scholar]. As highlighted by Sonkar et al., [[33]Sonkar V.K. Eustes A.S. Ahmed A. Jensen M. Solanki M.V. Swamy J. Kumar R. Fidler T.P. Houtman J.C.D. Allen B.G. Spitz D.R. Abel E.D. Dayal S. Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging.Arterioscler Thromb Vasc Biol. 2023; 43: 79-91Crossref PubMed Scopus (3) Google Scholar] their results are relevant in understanding the cardiovascular consequences of decreased SOD2 function in diverse populations (Summarized in Figure 2). Endogenous oxidative stress has long been known as a major determinant of aging [[46]Melov S. Ravenscroft J. Malik S. Gill M.S. Walker D.W. Clayton P.E. Wallace D.C. Malfroy B. Doctrow S.R. Lithgow G.J. Extension of life-span with superoxide dismutase/catalase mimetics.Science. 2000; 289: 1567-1569Crossref PubMed Scopus (774) Google Scholar,[47]Keaney M. Gems D. No increase in lifespan in Caenorhabditis elegans upon treatment with the superoxide dismutase mimetic EUK-8.Free Radic Biol Med. 2003; 34: 277-282Crossref PubMed Scopus (91) Google Scholar]. Several antioxidant nutrient supplements and mimetics have been considered for their therapeutic value in human diseases, including cancers and cardiovascular dysfunction [[48]Forman H.J. Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy.Nat Rev Drug Discov. 2021; 20: 689-709Crossref PubMed Scopus (396) Google Scholar,[49]Martemucci G. Portincasa P. Di Ciaula A. Mariano M. Centonze V. D'Alessandro A.G. Oxidative stress, aging, antioxidant supplementation and their impact on human health: an overview.Mech Ageing Dev. 2022; 206111707Crossref PubMed Scopus (7) Google Scholar]. Use of native SODs as therapeutics has shown limited promise, partly due to their larger molecular size (resulting in lower cell permeability), along with a limited circulating half-life [[46]Melov S. Ravenscroft J. Malik S. Gill M.S. Walker D.W. Clayton P.E. Wallace D.C. Malfroy B. Doctrow S.R. Lithgow G.J. Extension of life-span with superoxide dismutase/catalase mimetics.Science. 2000; 289: 1567-1569Crossref PubMed Scopus (774) Google Scholar]. By contrast, smaller compounds, such as the cyclic polyamine SOD mimetic GC4419, can overcome these limitations. Along with longer half-lives, these SOD mimetics provide a better access to cells, prevent immunogenic responses, and may be more cost effective [[50]Batinic-Haberle I. Reboucas J.S. Spasojevic I. Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential.Antioxid Redox Signal. 2010; 13: 877-918Crossref PubMed Scopus (397) Google Scholar]. Sonkar et al. [[33]Sonkar V.K. Eustes A.S. Ahmed A. Jensen M. Solanki M.V. Swamy J. Kumar R. Fidler T.P. Houtman J.C.D. Allen B.G. Spitz D.R. Abel E.D. Dayal S. Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging.Arterioscler Thromb Vasc Biol. 2023; 43: 79-91Crossref PubMed Scopus (3) Google Scholar] report that GC4419 considerably reduced the formation of procoagulant platelets and the thrombotic susceptibility in aged SOD2 KO and wild-type mice. Despite the lack of human data in their study, the authors suggest that the drug could be potentially useful in prevention of thrombotic complications in the aged population. GC4419, developed by Galera Therapeutics, is one of the many potential SOD mimetics that are being explored for their potential in limiting the oxidative stress associated with pathophysiologic conditions [[51]Heer C.D. Davis A.B. Riffe D.B. Wagner B.A. Falls K.C. Allen B.G. Buettner G.R. Beardsley R.A. Riley D.P. Spitz D.R. Superoxide dismutase mimetic GC4419 enhances the oxidation of pharmacological ascorbate and its anticancer effects in an H2O2-dependent manner.Antioxidants (Basel). 2018; 7: 18Crossref PubMed Scopus (29) Google Scholar]. It has already completed phase 1/2a clinical trials for use in chemotherapy and radiation treatment for squamous cell cancer and is currently in phase 2b clinical trials [[52]Sishc B.J. Ding L. Nam T.K. Heer C.D. Rodman S.N. Schoenfeld J.D. Fath M.A. Saha D. Pulliam C.F. Langen B. Beardsley R.A. Riley D.P. Keene J.L. Spitz D.R. Story M.D. Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide.Sci Transl Med. 2021; : 13Google Scholar]. Regarding antioxidant therapeutic strategies, the results from preclinical and clinical trials are conflicting [[53]Madamanchi N.R. Hakim Z.S. Runge M.S. Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes.J Thromb Haemost. 2005; 3: 254-267Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. Although the antioxidant mimetics are successful in ameliorating oxidative stress markers in mouse models and in vitro studies [[46]Melov S. Ravenscroft J. Malik S. Gill M.S. Walker D.W. Clayton P.E. Wallace D.C. Malfroy B. Doctrow S.R. Lithgow G.J. Extension of life-span with superoxide dismutase/catalase mimetics.Science. 2000; 289: 1567-1569Crossref PubMed Scopus (774) Google Scholar], their effect on limiting the disease progression is mostly negligible. Several randomized clinical trials using antioxidant supplements and/or mimetics have been disappointing. The potential reasons for failure remain complex and still poorly understood. This can be primarily attributed to the fact that although oxidative stress is a characteristic feature of several human diseases, including CVD, it does not necessarily form the major cause of the disease and may be a consequence of the disease. Moreover, diverse ROS species may be formed in different stages or etiologies of disease pathologies, and thus, a single antioxidant agent may not be sufficient for potential therapeutic benefit. Several ROS including O2•− and H2O2 play a role in physiological signaling, and thus, excessive scavenging of these signaling molecules can be detrimental. To add to the “antioxidant paradox,” it is likely that healthy subjects likely already have sufficient antioxidants and thus would exhibit a limited potential beneficial effect of supplemental antioxidant agents [[54]Halliwell B. The antioxidant paradox: less paradoxical now?.Br J Clin Pharmacol. 2013; 75: 637-644Crossref PubMed Scopus (226) Google Scholar]. With many of the SOD mimetics, such as GC4419, factors such as, pharmacokinetics (bioavailability), pharmacodynamics (culprit ROS species), route, and the timing of administration as per the disease pathology have not been clearly established despite some success in early phase clinical trials. With several SOD mimetics under consideration, dosing and the respective patient populations, need to be considered and duly compared while selecting one mimetic (or antioxidant enzyme) over the other. Despite all the strengths and limitations of clinical trials and research, it is clear that oxidative stress plays a pivotal role in the pathogenesis of CVD and hemostasis, and limiting oxidative stress is beneficial. Thus, antioxidant supplementation and use of antioxidant mimetics, such as SOD mimetics, does offer promise in diverse aging-related pathologies. However, there is an emerging need for careful evaluation of the use of these therapeutic agents for tailoring benefits in health and disease. Consideration should be given to the use of multiple antioxidants that may work in tandem to limit the differential effects of the reactive oxidants. Moreover, the choice of antioxidants, dose, and duration needs to be meticulously assessed. As is now evident, the indiscriminate use of antioxidants may not be favorable; instead, the antioxidant supplementation would only be likely beneficial when given to the right subject at the right time and for the right duration. Indeed, studies should include both human and mouse disease models to evaluate the potential value of new and existing antioxidants. Uniform guidelines about appropriate animal models and how these correspond to human aging and disease progression would be important for future studies that build on the present study by Sonkar et al. [[33]Sonkar V.K. Eustes A.S. Ahmed A. Jensen M. Solanki M.V. Swamy J. Kumar R. Fidler T.P. Houtman J.C.D. Allen B.G. Spitz D.R. Abel E.D. Dayal S. Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging.Arterioscler Thromb Vasc Biol. 2023; 43: 79-91Crossref PubMed Scopus (3) Google Scholar]. More exhaustive pharmacokinetics and toxicology studies need to be conducted for a conclusive consensus on the clinical needs and usage. The study by Sonkar et al. [[33]Sonkar V.K. Eustes A.S. Ahmed A. Jensen M. Solanki M.V. Swamy J. Kumar R. Fidler T.P. Houtman J.C.D. Allen B.G. Spitz D.R. Abel E.D. Dayal S. Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging.Arterioscler Thromb Vasc Biol. 2023; 43: 79-91Crossref PubMed Scopus (3) Google Scholar] highlights the importance of SOD2 in platelet mitochondrial function and thrombosis in aging, providing new directions in the development of antioxidant therapeutic strategies. The authors are supported by National Institutes of HealthNational Institutes of Health National Heart, Lung, and Blood Institute grants R01HL115247, R01HL122815, and R01HL150515 and T32HL007974 (to S.G.). K.J., S.G., and J.H. developed and wrote the manuscript. All authors read and approved the final paper. The authors declare no conflict of interest.