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Association between SOD2 T-9C and MTHFR C677T polymorphisms and longevity: a study in Jordanian population
© Khabour et al; licensee BioMed Central Ltd. 2009
Received: 20 July 2009
Accepted: 15 December 2009
Published: 15 December 2009
Aging in animals is associated with high body oxidative stress, which might affect susceptibility and onset of age-related diseases, and the subsequent life span. Therefore, genes that modulate oxidative stress might play a role in determining longevity. In this study, we investigated whether the gene pool relevant to the SOD2-9T/C and MTHFR 677C/T polymorphisms changes as the Jordanian population ages.
Polymorphisms were genotyped in 130 elderly subjects (57 females and 73 males, mean age: 90.01 years) and 135 young control subjects (67 females and 68 males, mean age: 33.43 years).
No significant differences were found in the genotype and allele frequencies of examined SOD2 and MTHFR gene variants between the elderly group and young controls (P > 0.05), nor when each gender was considered separately (P > 0.05).
SOD2-9T/C and MTHFR 677C/T gene polymorphisms do not seem to be important in Jordanian population for longevity phenotype.
Aging involves increases in oxidative stress status presented by elevated levels of oxidized forms of biomolecules in the body of the organism . This leads to tissue damage and decreases in body functions, homeostasis, and tolerance to chronic diseases [2, 3]. Thus, genes that modulate oxidative stress might play a role in human longevity.
In this study, we investigated association of SOD2 -9T/C SNP and MTHFR 677 C/T SNP with longevity in Jordanian population. The SOD2 gene codes for the mitochondrial manganese superoxide dismutase, a major cellular antioxidative stress enzyme . SOD2 dismutates the superoxide anion into hydrogen peroxide that is detoxified into water by glutathione peroxidases and catalase . Presence of the C allele at -9 position of SOD2 gene results in substitution of alanine for valine (Ala16Val) in the mitochondrial targeting sequence . This substitution partially retains SOD2 enzyme within the narrow inner membrane import pore and lowers the enzyme activity [7, 8]. The importance of SOD2 -9T/C polymorphism is indicated by its association with several age related diseases such as cancer [9, 10] and diabetic nephropathy .
The MTHFR gene codes for methylenetetrahydrofolate reductase that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter serves as a methyl donor in the reaction converting homocysteine to methionine . The T allele at 677 position of MTHFR gene causes substitution of alanine to valine and the resulting decreases in enzyme activity and increases in body homocysteine concentrations . Excess homocysteine undergoes auto-oxidation in plasma, so that free oxygen radicals are produced thereby enhancing endothelial tissue damage and inflammation . In addition, excess homocysteine can directly impair DNA methylation, resulting in altered gene expression . The MTHFR 677 C/T polymorphism has been shown to be associated with ischemic stroke , cancer  and coronary artery disease .
Previous reports are variable on the association between SOD2 -9 SNP or MTHFR 677 SNP with human longevity. For example, positive association has been reported between SOD2 -9 SNP and Ashkenazi males , but not Italian population . Similarly, positive association has been reported between MTHFR SNP, and Swiss population or Ashkenazi women [19, 21], but not Irish population . In this study, we report absence of association between -9 T/C SOD2 SNP or 677 C/T MTHFR SNP with longevity in the examined sample of Jordanian elderly.
One hundred thirty unrelated elderly subjects (> 85 years, mean age 90.01 year) volunteered from different parts of Jordan to take part in this study. Another 135 unrelated young control subjects (range from 20 to 50 years, mean age 33.34 years) were matched long-lived individuals for geographical origin. Subjects with cardiovascular diseases, diabetes, or cognitive impairments were excluded from the study. The experimental design and the sample size were similar to most longevity studies reviewed by Glatt et al., . Subject's mean ages were selected based on the mortality rate in the Jordanian population, which is approximately constant from childhood to late forties, thereafter, it starts gradually inclining to reach maximum in late seventies . Therefore, individuals who reach more than 85 years are rare in Jordan. An official identification document was required to participate in the study. Acceptable documents include civil ID card, birth certificate, family book, passport and military card, otherwise enrolment in the study was denied. All subjects received written and verbal explanation of the study before giving consent. The study protocol was approved by the Institutional Review Boards of Jordan University of Science and Technology.
Blood samples (1-3 ml) in EDTA tubes were obtained from all subjects. DNA was extracted from all samples using Wizard DNA Extraction Kit (Promega, Madison, USA) according to the manufacturer instructions. DNA samples were stored at -20°C until used. The concentration of the extracted DNA was measured using SmartSpect™ 3000 (Bio-Rad, Hertfordshire, UK).
SOD2 T-9C polymorphism was typed using RFLP-PCR protocol. Briefly, 20 μl reaction mixture containing 5 ng of template DNA, 0.75 unit GoTaq polymerase (Promega, Madison, USA), and a final concentration of 200 mM each deoxynucleotide and 1× reaction buffer, and 1 mM of forward (5'-ACC AGC AGG CAG CTG GCG CCG G-3') and reverse (5'-GCG TTG ATG TGA GGT TCC AG-3') primers. Cycling was performed at 95°C for 15 min and 35 cycles at 94°C for 30 s, 65°C for 30 s and 72°C for 30 s, followed by a final extension of 7 min at 72°C. PCR products were detected using electrophoresis on 4% agarose, confirming the presence of a 107 bp product. The NgoMIV enzyme (Fermentas. GmbH, St. Leon-Rot, Germany) digestion was carried out in 20 ul reaction mixture containing 3 units of enzyme and 10 μl of PCR product at 37°C for 4 hours. Materials from individuals homozygous for SOD2 -9 T allele don't cut with NgoMIV and remain as a 107 bp product. The homozygous SOD2 -9 C allele cuts with NgoMIV to give 89 bp and 18 bp fragments.
The MTHFR C677T polymorphism was also analyzed by PCR-RFLP using Hinf I enzyme (Fermentas). PCR primers were: forward primer (5'-TGA AGG AGA AGG TGT CTG CGG GA-3') and reverse primer (5'-AGG ACG GTG CGG TGA GAG TG-3'). Polymerase chain reaction and Hinf I digestion condition were similar to that described for SOD2 -9 SNP except for the annealing temperature, which was 60°C in this case. PCR fragments from MTHFR 677 C allele don't cut with Hinf I and remain as a 198 bp product while fragments from MTHFR 677 T allele cut with Hinf I to give 175 bp and 23 bp fragments.
The genotype distributions of the examined polymorphisms were analyzed in agreement with Hardy-Weinberg equilibrium. To test association between longevity and the polymorphic loci, distributions of allele and genotype frequencies were compared between young and elderly groups using the chi-square and Fisher's exact tests. The test power was calculated for alleles frequency using Power and Sample Size Calculation Program (PS version 3.0.1, Vanderbilt University Medical Center, Nashville, TN, USA) and for genotype frequencies using SAS macro . For all analysis, the power was more than 75%. The SPSS 15.0 statistical software package (SPSS Inc., Chicago, IL) was used for statistical analysis. P values smaller than 0.05 were considered significant.
Jordan is a small country located in Southwest Asia and classified among the low income countries. The population is predominantly Arab (98%) and most of it is urban (70%) . According to the 2007 census, the total population of Jordan was 5.7 million, percentage of individuals of 65 years of age or older was 4.1% and life expectancy at birth in the total population was 73 year .
The average age of the elderly group in the study was 90.01 years. In Jordan, the mortality rate starts inclining exponentially at fifty year-old getting maximum level in the late seventies indicating that reaching above 85 year-old is a rarity (Khoury et al., 1999). Therefore, oldest old people (> 85 year-old) are considered exceptional individuals in Jordan.
Males to females ratio was 1.3:1 in the elderly group and 1:1 in the control group (P = 0.346). Number of relatives who exceeded 85 year-old was higher in the elderly group compared to the young control group (70.3% versus 59.8%, respectively, P = 0.013). The higher number of relatives who exceeded 85 year-old (>25%) in the elderly group indicates the presence of genetic component to longevity in the Jordanian population.
Frequencies of SOD2 and MTHFR alleles and genotypes in elderly and control groups.
Genotypes and Alleles
-9 SOD2 *
677 MTHFR *
Frequencies of SOD2 and MTHFR alleles and genotypes in elderly and control male subjects
Genotypes and Alleles
Control males group
Elderly males group
Frequencies of SOD2 and MTHFR alleles and genotypes in elderly and control female subjects
Genotypes and Alleles
Control Females group
Elderly Females group
Oxidative stress is a condition where the redox balance between oxidant and antioxidant is shifted toward an oxidized state. In animals, oxidative stress increase with ageing due to high production of free radicals by aged mitochondria and decreased cellular antioxidant capacity. The mitochondrial magnesium superoxide dismutase (SOD2) is considered the first line of defense against reactive oxygen species . The gene for SOD2 has a common T to C polymorphism, resulting in a valine to alanine change at the 16 position of its mitochondrial targeting sequence (Ala16Val), which affects the structure of the protein , and reduces its entrance into the mitochondria  leading to increased oxidative stress.
The MTHFR gene also affects oxidative stress status in human body. The gene codes for an enzyme that play a key role in the folate metabolism . Nucleotide transition (C to T) at nucleotide 677 of MTHFR causes alanine to valine substitution in the N-terminal catalytic domain, leading to 30% and 65% reduction in activity for heterozygotes and homozygotes of the variant allele, respectively . Reduced activity of MTHFR leads to high levels of blood homocysteine, which is rapidly auto-oxidized, leading to the production of cytotoxic reactive oxygen species and to endothelial damage .
In this study, we hypothesized that the presence of the C allele at -9 position of SOD2 and T allele at position 677 of MTHFR might decrease life span. The data showed no statistically significant difference between the elderly and young groups when comparing genotypic distributions and allelic frequencies of studied SOD2 and MTHFR polymorphisms (Table 1). In agreement with our results, De Benedictis et al.,  showed that SOD2 variant does not affect individual life expectancy in Italian population (sample size: 109, age criterion > 100 years old). In addition, Brattstrom et al.,  reported that MTHFR C677T allele is not a strong risk factor for premature death in Ireland (sample size: 1388, age criterion > 80 years old). In animal models, mice deficient in SOD2 (Sod2-/-) exhibit neonatal lethality in association with dilated cardiomyopathy and a massive lipid accumulation in the liver , while (Sod2+/-) heterozygous mice have increased cancer incidence without affecting aging . Furthermore, SOD isoforms showed no effect on life span in C. elegans  and Drosophila . In contrast to our results, positive association has been reported in Danish population (sample size: 1650, age criterion > 92 years old)  and Ashkenazi males (sample size 150, > 75 years old  with SOD2 -9 SNP, while for MTHFR, positive association has been reported in Swiss population (sample size: 104, age criterion > 65 years old) and Ashkenazi women (sample size: 74, age criterion > 75 years old) [19, 21]. The discrepancy in the finding of the different studies might be due to difference in experimental design, sample size and criteria used in selecting subjects. In addition, the examined polymorphisms/longevity associations might have a population specific component, being affected by the population specific gene pool as well as by gene-environment interaction.
Among the limitations of this study are the sample size and age of recruitments of elderly subjects (≥ 85 years). One hundred and thirty subjects with a mean age of 90.01 years were included in the present study. The population of Jordan was 5.7 million in 2007 and only 4.1% of the total population was individuals of 65 years of age or older . In addition, the mortality rate starts inclining exponentially at fifty year-old getting maximum level in the late seventies indicating that reaching above 85 year-old is a rarity (Khoury et al., 1999). Therefore, oldest old people are considered exceptional individuals in Jordan. Moreover, the lack of elderly centers in Jordan makes it very hard to recruit elderly subjects that fit sampling criteria. Despite all these obstacles, the sample size of the current research fall within the range of longevity studies reviewed by Glatt et al.,  and previous studies that asked the same question in other populations (see discussion above). Future studies with a bigger sample size might be more appropriate with this kind of research.
Longevity is a complex trait, which likely results from a blessed combination of genetic and non-genetic factors . It is possible that the excess of environmental factors exert stronger influence on longevity than the genetic traits . For example, in institutionalized or home-bound elderly, oxidative stress was reported to increase significantly [40, 41], while in free living elderly it is not always elevated . In addition, MTHFR C677T polymorphism effect on homocysteine level can be minimized by folate intake. Studies attempting to assess the overall genetic influence on variations in the human life span indicated that approximately a quarter of the variation in the adult life spans could be attributed to genetic variation among individuals . Thus, the strong influence of environmental factors on longevity might wipe the most likely weaker effect of genetic factors as observed in this study. However, the result which shows that number of relatives who exceeded 85 year-old was higher in the elderly group by approximately 25% compared to the young control group indicates the presence of genetic component to longevity in the Jordanian population. It is possible that other polymorphisms are present in the region of the examined genes in the Jordanian population; this might buffer out or modulate the effect of the studied loci. Therefore, further studies are required to screen for the presence of such modifier polymorphisms in addition to direct measurement of levels and activity of gene products of the examined loci in according to subject's genetic background.
Reaching extreme age without diseases is one aspect of successful ageing . In this study, elderly individuals with cardiovascular diseases, diabetes, or cognitive impairments were excluded from the current study. Previous studies have shown that SOD2 -9T/C and MTHFR 677 C/T polymorphisms were associated with diabetes, cancer and cardiovascular diseases in other populations [9, 10]. Thus, these polymorphisms might also associate with certain diseases in the Jordanian population. Exploring this possibility is a matter of future research.
In this study, we investigated the contribution of the SOD2-9T/C and MTHFR 677C/T gene polymorphisms to the longevity phenotype in the Jordanian population. The results of this study indicate that SOD -9T/C and MTHFR 677C/T are not important determinant of life span in Jordanian population.
This work has been done with funds from the Deanship of Scientific Research in Jordan University of Science and Technology, grant number 182/2007 to OK. The authors thank Dr. Karem Al-Zoubi for his comments on the manuscript.
- Shringarpure R, Davies KJ: Protein turnover by the proteasome in aging and disease. Free Radic Biol Med. 2002, 32 (11): 1084-1089. 10.1016/S0891-5849(02)00824-9.View ArticlePubMedGoogle Scholar
- Kregel KC, Zhang HJ: An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol. 2007, 292 (1): R18-36.View ArticlePubMedGoogle Scholar
- Tsubota K: [Oxidative stress and inflammation: hypothesis for the mechanism of aging]. Nippon Ganka Gakkai Zasshi. 2007, 111 (3): 193-205. discussion 206PubMedGoogle Scholar
- Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow SR, Lithgow GJ: Extension of life-span with superoxide dismutase/catalase mimetics. Science. 2000, 289 (5484): 1567-1569. 10.1126/science.289.5484.1567.View ArticlePubMedGoogle Scholar
- Zelko IN, Mariani TJ, Folz RJ: Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002, 33 (3): 337-349. 10.1016/S0891-5849(02)00905-X.View ArticlePubMedGoogle Scholar
- Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-Hattori Y, Shimizu Y, Mizuno Y: Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochem Biophys Res Commun. 1996, 226 (2): 561-565. 10.1006/bbrc.1996.1394.View ArticlePubMedGoogle Scholar
- Martin RC, Li Y, Liu Q, Jensen NS, Barker DF, Doll MA, Hein DW: Manganese Superoxide Dismutase V16A Single-Nucleotide Polymorphism in the Mitochondrial Targeting Sequence Is Associated with Reduced Enzymatic Activity in Cryopreserved Human Hepatocytes. DNA Cell Biol. 2008, 10.1089/dna.2008.0788.Google Scholar
- Sutton A, Imbert A, Igoudjil A, Descatoire V, Cazanave S, Pessayre D, Degoul F: The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics. 2005, 15 (5): 311-319. 10.1097/01213011-200505000-00006.View ArticlePubMedGoogle Scholar
- Chan JM, Oh WK, Xie W, Regan MM, Stampfer MJ, King IB, Abe M, Kantoff PW: Plasma Selenium, Manganese Superoxide Dismutase, and Intermediate- or High-Risk Prostate Cancer. J Clin Oncol. 2009, 27 (22): 3577-3583. 10.1200/JCO.2008.18.8938.View ArticlePubMedPubMed CentralGoogle Scholar
- Zejnilovic J, Akev N, Yilmaz H, Isbir T: Association between manganese superoxide dismutase polymorphism and risk of lung cancer. Cancer Genet Cytogenet. 2009, 189 (1): 1-4. 10.1016/j.cancergencyto.2008.06.017.View ArticlePubMedGoogle Scholar
- el-Masry TM, Zahra MA, el-Tawil MM, Khalifa RA: Manganese superoxide dismutase alanine to valine polymorphism and risk of neuropathy and nephropathy in Egyptian type 1 diabetic patients. Rev Diabet Stud. 2005, 2 (2): 70-74. 10.1900/RDS.2005.2.70.View ArticlePubMedPubMed CentralGoogle Scholar
- Aguilar B, Rojas JC, Collados MT: Metabolism of homocysteine and its relationship with cardiovascular disease. J Thromb Thrombolysis. 2004, 18 (2): 75-87. 10.1007/s11239-004-0204-x.View ArticlePubMedGoogle Scholar
- Cortese C, Motti C: Gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutr. 2001, 4 (2B): 493-497. 10.1079/PHN2001159.View ArticlePubMedGoogle Scholar
- Oikawa S, Murakami K, Kawanishi S: Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. Oncogene. 2003, 22 (23): 3530-3538. 10.1038/sj.onc.1206440.View ArticlePubMedGoogle Scholar
- Jamaluddin MS, Yang X, Wang H: Hyperhomocysteinemia, DNA methylation and vascular disease. Clin Chem Lab Med. 2007, 45 (12): 1660-1666. 10.1515/CCLM.2007.350.View ArticlePubMedGoogle Scholar
- Djordjevic V, Stankovic M, Brankovic-Sreckovic V, Rakicevic L, Radojkovic D: Genetic Risk Factors for Arterial Ischemic Stroke in Children: A Possible MTHFR and eNOS Gene-Gene Interplay?. J Child Neurol. 2009, 24 (7): 823-827. 10.1177/0883073808330164.View ArticlePubMedGoogle Scholar
- Gallegos-Arreola MP, Garcia-Ortiz JE, Figuera LE, Puebla-Perez AM, Morgan-Villela G, Zuniga-Gonzalez GM: Association of the 677C ->T Polymorphism in the MTHFR Gene with Colorectal Cancer in Mexican Patients. Cancer Genomics Proteomics. 2009, 6 (3): 183-188.PubMedGoogle Scholar
- Sarecka-Hujar B, Zak I, Krauze J: Carrier-state of two or three polymorphic variants of MTHFR, IL-6 and ICAM1 genes increases the risk of coronary artery disease. Kardiol Pol. 2008, 66 (12): 1269-1277.PubMedGoogle Scholar
- Stessman J, Maaravi Y, Hammerman-Rozenberg R, Cohen A, Nemanov L, Gritsenko I, Gruberman N, Ebstein RP: Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. Mech Ageing Dev. 2005, 126 (2): 333-339. 10.1016/j.mad.2004.08.025.View ArticlePubMedGoogle Scholar
- De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Cavalcanti S, Corsonello F, Feraco E, Baggio G, et al: Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet. 1998, 6 (6): 534-541. 10.1038/sj.ejhg.5200222.View ArticlePubMedGoogle Scholar
- Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE: Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest. 1999, 29 (12): 1003-1009. 10.1046/j.1365-2362.1999.00578.x.View ArticlePubMedGoogle Scholar
- Brattstrom L, Zhang Y, Hurtig M, Refsum H, Ostensson S, Fransson L, Jones K, Landgren F, Brudin L, Ueland PM: A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis. 1998, 141 (2): 315-319. 10.1016/S0021-9150(98)00154-3.View ArticlePubMedGoogle Scholar
- Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV: Successful aging: from phenotype to genotype. Biol Psychiatry. 2007, 62 (4): 282-293. 10.1016/j.biopsych.2006.09.015.View ArticlePubMedGoogle Scholar
- Khoury SA, Massad D, Fardous T: Mortality and causes of death in Jordan 1995-96: assessment by verbal autopsy. Bull World Health Organ. 1999, 77 (8): 641-650.PubMedPubMed CentralGoogle Scholar
- Ozdimer T, Keskin S, Cak B: Calculation of Power in chi-square and Likelihood ratio chi-square statistics by a special SAS macro. Pakistan Journal of Biological Sciences. 2006, 9 (15): 4-Google Scholar
- Department of Statistics: Jordan in numbers. [http://www.dos.gov.jo/jorfig/2007/jor_f_a.htm]
- Cederholm T, Persson M, Andersson P, Stenvinkel P, Nordfors L, Madden J, Vedin I, Wretlind B, Grimble RF, Palmblad J: Polymorphisms in cytokine genes influence long-term survival differently in elderly male and female patients. J Intern Med. 2007, 262 (2): 215-223. 10.1111/j.1365-2796.2007.01803.x.View ArticlePubMedGoogle Scholar
- Lio D, Scola L, Crivello A, Colonna-Romano G, Candore G, Bonafe M, Cavallone L, Franceschi C, Caruso C: Gender-specific association between -1082 IL-10 promoter polymorphism and longevity. Genes Immun. 2002, 3 (1): 30-33. 10.1038/sj.gene.6363827.View ArticlePubMedGoogle Scholar
- Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F: Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics. 2003, 13 (3): 145-157. 10.1097/00008571-200303000-00004.View ArticlePubMedGoogle Scholar
- Lewis SJ, Ebrahim S, Davey Smith G: Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. BMJ. 2005, 331 (7524): 1053-10.1136/bmj.38611.658947.55.View ArticlePubMedPubMed CentralGoogle Scholar
- Weisberg I, Tran P, Christensen B, Sibani S, Rozen R: A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998, 64 (3): 169-172. 10.1006/mgme.1998.2714.View ArticlePubMedGoogle Scholar
- Chwatko G, Boers GH, Strauss KA, Shih DM, Jakubowski H: Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 2007, 21 (8): 1707-1713. 10.1096/fj.06-7435com.View ArticlePubMedGoogle Scholar
- Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, et al: Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995, 11 (4): 376-381. 10.1038/ng1295-376.View ArticlePubMedGoogle Scholar
- Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, et al: Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003, 16 (1): 29-37. 10.1152/physiolgenomics.00122.2003.View ArticlePubMedGoogle Scholar
- Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D: Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev. 2008, 22 (23): 3236-3241. 10.1101/gad.504808.View ArticlePubMedPubMed CentralGoogle Scholar
- Paul A, Belton A, Nag S, Martin I, Grotewiel MS, Duttaroy A: Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging. Mech Ageing Dev. 2007, 128 (11-12): 706-716. 10.1016/j.mad.2007.10.013.View ArticlePubMedPubMed CentralGoogle Scholar
- Soerensen M, Christensen K, Stevnsner T, Christiansen L: The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old. Mech Ageing Dev. 2009, 130: 6-Google Scholar
- Dossey L: Longevity. Altern Ther Health Med. 2002, 8 (3): 12-16. 125-134Google Scholar
- Deiana L, Ferrucci L, Pes GM, Carru C, Delitala G, Ganau A, Mariotti S, Nieddu A, Pettinato S, Putzu P, et al: AKEntAnnos. The Sardinia Study of Extreme Longevity. Aging (Milano). 1999, 11 (3): 142-149.Google Scholar
- Glynn SA, Boersma BJ, Howe TM, Edvardsen H, Geisler SB, Goodman JE, Ridnour LA, Lonning PE, Borresen-Dale AL, Naume B, et al: A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide. Clin Cancer Res. 2009, 15 (12): 4165-4173. 10.1158/1078-0432.CCR-09-0119.View ArticlePubMedPubMed CentralGoogle Scholar
- Maugeri D, Santangelo A, Bonanno MR, Testai M, Abbate S, Lo Giudice F, Mamazza C, Pugllsi N, Panebianco P: Oxidative stress and aging: studies on an East-Sicilian, ultraoctagenarian population living in institutes or at home. Arch Gerontol Geriatr Suppl. 2004, 271-277. 10.1016/j.archger.2004.04.037. 9Google Scholar
- Andriollo-Sanchez M, Hininger-Favier I, Meunier N, Venneria E, O'Connor JM, Maiani G, Coudray C, Roussel AM: Age-related oxidative stress and antioxidant parameters in middle-aged and older European subjects: the ZENITH study. Eur J Clin Nutr. 2005, 59 (Suppl 2): S58-62. 10.1038/sj.ejcn.1602300.View ArticlePubMedGoogle Scholar
- Karasik D, Demissie S, Cupples LA, Kiel DP: Disentangling the genetic determinants of human aging: biological age as an alternative to the use of survival measures. J Gerontol A Biol Sci Med Sci. 2005, 60 (5): 574-587.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/9/57/prepub
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