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Hindawi Publishing Corporation Current Gerontology and Geriatrics Research Volume 2010, Article ID 380460, 10 pages doi:10.

1155/2010/380460

Research Article Oxidative Stress and Longevity in Okinawa: An Investigation of Blood Lipid Peroxidation and Tocopherol in Okinawan Centenarians
Makoto Suzuki,1, 2, 3 D. Craig Willcox,1, 2, 4 Matthew W. Rosenbaum,1 and Bradley J. Willcox1, 4, 5, 6, 7
1 Okinawa

Research Center for Longevity Science, Okinawa 901-2114, Japan of Human Welfare, Okinawa International University, Okinawa 901-2701, Japan 3 Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan 4 Pacific Health Research and Education Institute, Honolulu, HI 96813, USA 5 Department of Research, Kuakini Medical Center, Honolulu, HI 96817, USA 6 Department of Research, Planning and Development, The Queen’s Medical Center, Honolulu, HI 96813, USA 7 Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, HI 96817, USA
2 Department

Correspondence should be addressed to Makoto Suzuki, orcls@nirai.ne.jp and Bradley J. Willcox, willcoxbj@gmail.com Received 16 August 2010; Accepted 30 November 2010 Academic Editor: Leonard W. Poon Copyright © 2010 Makoto Suzuki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. The Free Radical Theory of Aging mechanistically links oxidative stress to aging. Okinawa has among the world’s longest-lived populations but oxidative stress in this population has not been well characterized. Methods. We compared plasma lipid peroxide (LPO) and vitamin E—plasma and intracellular tocopherol levels (total α, β, and γ), in centenarians with younger controls. Results. Both LPO and vitamin E tocopherols were lower in centenarians, with the exception of intracellular βtocopherol, which was significantly higher in centenarians versus younger controls. There were no significant differences between age groups for tocopherol: cholesterol and tocopherol: LPO ratios. Correlations were found between α-Tocopherol and LPO in septuagenarians but not in centenarians. Conclusions. The low plasma level of LPO in Okinawan centenarians, compared to younger controls, argues for protection against oxidative stress in the centenarian population and is consistent with the predictions of the Free Radical Theory of Aging. However, the present work does not strongly support a role for vitamin E in this phenomenon. The role of intracellular β-tocopherol deserves additional study. More research is needed on the contribution of oxidative stress and antioxidants to human longevity.

1. Introduction
Human longevity is a complex phenotype that is determined by environment, genetics, and chance [1]. Understanding the mechanisms by which aging leads to longevity, particularly healthy longevity would be of enormous benefit to our aging population. Unfortunately, most research on human aging has focused on phenomenological description of age-related diseases, and much less is known about the mechanisms of aging itself [2]. Among the most promising theories about how and why we age is the Free Radical Theory, initially proposed by Denham Harman in 1956 [3].

Harman proposed that oxygen radicals produced during aerobic respiration induce oxidative damage in DNA, cells, tissues, and organisms that lead to aging and death. Studies in Harman [3] hypothesized, based on observations of enzymatic redox chemistry, that oxygen radical generation occurs in vivo and that mechanisms exist to protect against such damage. Mitochondria were later found to be a principal source of these oxygen radicals [4]. The enzyme superoxide dismutase (SOD) provided early evidence for endogenous antioxidant defenses against such radical damage [5]. Exogenous antioxidant defenders have also been discovered in food sources, among the most studied being vitamin E [6, 7].

it is possible that intracellular concentrations of vitamin E (or its subtypes) may be more important than plasma vitamin E. As an important fat soluble antioxidant. eighties) participants.g. a common antioxidant. 79 healthy community-dwelling people (34 males. while the reminder consisted of 8. Suzuki et al. residing in Okinawa. where they were separated into plasma and blood cell components by centrifugation. who are more likely to consume a traditional diet [13]. [14] studied whether Okinawan centenarians also displayed high levels of plasma or intracellular SOD. in part. and tocotrienols can protect neurons from oxidative stress [8–10].5 years) were recruited and subjected to identical examinations under similar conditions. was significantly lower in the plasma of centenarians than of younger controls. mean age 62. activity of daily living survey. is consumed in quite high quantity. and 1. Since the major exposure to oxidative stress in humans originates from mitochondria and this stress occurs mainly intracellularly. Based on this background. vitamin E intake is known to be high in the traditional Okinawan diet due to abundant consumption of foods such as soy beans (tofu and soy bean oils). seventies. such as centenarians. are rich in β-tocopherol. Nevertheless.8% δ-tocopherol. 20] showed in prior work that vitamin E. Additional younger controls were recruited for comparison purposes in the current study. sweet potatoes. we and others have investigated LPO. This is reflected in relatively high plasma α-tocopherol in older Okinawans. 109 females. Vitamin E and/or its various tocopherols could theoretically explain the low LPO in Okinawan centenarians. 2. mustard greens. For the control group. which is more likely to be consumed by centenarians [19]. 14. Few foods have a significant quantity of β-tocopherol [18] but some traditional Okinawan foods. and vitamin E as potential factors in human aging and longevity. Materials and Methods This study was conducted under ongoing Institutional Review Board approval from Okinawa International University. This might be. For example. and anthropometric measurements. [12] found that lower plasma lipid peroxide and higher plasma vitamin E predicted lower risk of cardiovascular events (an important cause of premature mortality) in healthy Italian octogenarians over a 4-year period. Therefore. consistent with their demographic selection against mortality.3 years). were previously studied and had banked blood samples [20]. β-tocopherol has similar properties. A total of 139 centenarians (30 males. This was despite the fact that few Okinawans consumed vitamin supplements while more than a third of US elders did.2 Vitamin E consists of a group of eight related fat soluble tocopherols and tocotrienols. and informed consent was received from all study participants.. In order to assess potential connections between LPO and common endogenous or exogenous antioxidants. Total numbers of cases and controls varied according to the particular assay performed. and green leafy vegetables (e. Conversely. (2) to quantify blood and intracellular levels of vitamin E (measured in red blood cells). A recent comparative study found that mean α-tocopherol levels were similar between Okinawan elderly and healthy elderly from the USA (Oregon) with and without adjustments for total cholesterol or triglycerides [16]. Some research supports α-tocopherol as the most important lipid soluble antioxidant since it protects cell membranes from chain reactions caused by radical-induced lipid peroxidation through quenching free radical intermediates [7]. and metabolization occur with α-tocopherol [7]. aged 20–80. For example. (3) to assess potential correlations between LPO and vitamin E levels. SOD levels were lower in centenarians than in younger controls. a reaction to low levels of oxidative stress in centenarians but it does not offer support for SOD as a major protector against oxidative stress in this population. 16]. Current Gerontology and Geriatrics Research Foods also vary markedly in their tocopherol content.7% β-tocopherol [17]. [13. A physical examination was performed at the participants’ place of residence. Studies in Suzuki et al.5% γ-tocopherol. α-tocopherol is typically the most abundant tocopherol in human serum since it is preferentially conserved by the liver. while not as β-tocopherolrich. While the antioxidant role of other forms of vitamin E is less clear. Examination included hematological and biochemical analysis of blood. [13] found that plasma LPO was lower in Okinawan centenarians than septuagenarians. papaya (and its leaves). swiss chard. Blood samples were taken in EDTA tubes and stored on ice. even after adjustment for lipids and other factors. one study of middle-aged Japanese women found that α-tocopherol formed 88% of serum tocopherol. vitamin E subtypes (tocopherol subtypes) and/or intracellular tocopherol levels were not studied. other soy foods and cooking oil). spinach. a common proxy measure of oxidative stress. like SOD. we studied Okinawan centenarians and younger control populations with the following primary aims: (1) to quantify blood levels of lipid peroxide (LPO). 1. soy oil is mainly γ-tocopherol (>60%) whereas sunflower oil is mainly α-tocopherol (>90%) [17]. Plasma LPO has been found to increase with age into the septuagenarian years [11] but little is known about population levels in exceptionally aged individuals. Suzuki et al. Studies in Mezzetti et al. These controls consisted of younger (twenties. which have significant antioxidant properties [6]. This is consistent with the hypothesis that protection against oxidative stress might be a survival factor in older Okinawans and possibly a marker of “slower” aging. particularly in the traditional Okinawan diet. thirties) and older (sixties. mean age = 100. γ-tocopherol is a nucleophile that can quench electrophilic mutagens. absorption. Ultracentrifugation was used to evaluate plasma total cholesterol and cholesterol subfractions. Samples were then transported to the University of the Ryukyus Hospital. and numerous other local varieties) [15. LPO was measured using the thiobarbituric acid (TBA) reaction for fatty acid oxidation . including brown seaweed and hot red peppers. SOD. However. soy oil (in tofu. Contrary to expectations. 45 females. The highest bioavailability.

31 μg/ml for males (n = 19) and 11.00 ± 1. females (2. seventies (n = 29.10 ± 0.Current Gerontology and Geriatrics Research otherwise known as the “TBA method” [21. For both genders α-tocopherol tended to increase with age and peak at septuagenarian years.42 μg/ml. γ-Toco) was also compared between age groups by gender.72 ± 1.08. Intracellular Ttocopherol in centenarian red blood cells in males (1. Levels tended to peak in the septuagenarian years for the combined group and were less reliable in individual groups.05 (octogenarians) to P < . Plasma α-tocopherol in centenarian males (7. P < .05) and α-tocopherol (P < . α-tocopherol.35. and γtocopherol in centenarians versus a younger control group (septuagenarians) separated by gender and adjusted for plasma total cholesterol (Tc) and HDL cholesterol (HDLC) by dividing tocopherol levels by cholesterol levels. Peak values tended to be reached in octogenarian years in females with no clear pattern in males until a sharp decline in centenarians of both genders. This was likely due to the small numbers of study participants in individual age groups other than the septuagenarian age group. β-.34. This comparison was important since differences in tocopherol between age groups might be an artifact of differences in plasma lipid levels that occur commonly with age. and both sexes combined (2. Comparisons of centenarians across age strata within gender groups were significant between septuagenarians in females and between all age groups in males.59 μg/ml.001).24 ± 0. n = 74).001). since concentrations did not appear to be different across age strata until centenarian years.80 ± 1. centenarian females (1. and 10.04 μg/ml.10 μg/ml. Similar relations were seen as with α-tocopherol where peak values appeared in the septuagenarian years and dropped rapidly thereafter. P < .91 ± 0.22 μg/ml. and combined total (9. We also compared the levels of plasma tocopherol subtypes (α-. n = 96) was significantly lower than in all other age groups for combined genders versus all individual age strata (P < .32 for both groups combined (n = 110). Results Table 1 demonstrates that plasma LPO levels of centenarians were 1. which may partly reflect malnutrition [24]. n = 92) appeared lower than all other age groups. with combined plasma α-tocopherol level in centenarians significantly lower than in younger age groups across all age strata (significance levels ranged from P < . and both sexes combined (0. Total plasma β-tocopherol levels in centenarian males (0. samples were frozen on dry ice and sent to Eizai Research Institute. n = 37).05) centenarian groups. only the difference between centenarians and controls in their seventies was significant (P < .001). However. possibly due to small numbers. .25. most tocopherol is carried in lipid subfractions and therefore might appear artificially low if not adjusted by plasma lipid levels. Table 3 demonstrates comparisons between intracellular tocopherol levels (total and by subtype) between centenarians and controls in various age strata. Older populations (age 70 years or more) tend to have lower cholesterol levels. n = 10). In centenarians. β-Toco.28 nmol/ml for females (n = 109).05 ± 3. Centenarian plasma T-tocopherol (males and females combined) was significantly lower than that of every younger age group (P < . then dropped rapidly thereafter. P < .07 μg/ml.20 ± 0. However. significance levels ranged from P < .51 nmol/ml in males (n = 30). females (0.82 ± 3.08 ± 0.51 ± 0.19 μg/ml. and gender combined total (0.07 μg/ml. 3 Gender-related differences appeared with significantly higher T-tocopherol (P < .79.67 ± 1. n = 69).20 ± 0. thirties (n = 16.001). females (0. α-tocopherol levels in males (1. 3. This was partly limited by small numbers. with T-tocopherol increasing with age in both genders until the age of 70s and then dropping thereafter. n = 87) were significantly lower than in septuagenarians but not in other age groups (male P < . For tocopherol studies. This trend generally held true for both genders as well.01).19 μg/ml.01 ± 0.89±1. and both genders combined (1.25 ± 0.08 μg/ml.01 combined). This relation held when separated by gender for most individual age groups.05). P < .19 μg/ml. n = 19). P < . γ-tocopherol) in centenarians to younger controls. Table 2 displays average (mean) plasma tocopherol levels (total and by subtype) across age strata. and 1. n = 47) was the highest of all age groups. Table 4 demonstrates T-tocopherol. n = 77).05. n = 77).30 ± 1. Total plasma tocopherol (T-Toc) in centenarians was 8.89 ± 2.001).05 males. Lack of significant difference between centenarians and other groups may have been influenced by small numbers of participants in comparison groups.001).18 ± 0.05) and septuagenarian sexes combined (P < .84 μg/ml.001). n = 18).01 females. 2.001 (septuagenarians).79 ± 2.30 ± 1.16 nmol/ml overall (n = 139).03 ± 0. n = 19).32 μg/ml.23 ± 0. Plasma γ-tocopherol levels for centenarian males (0. n = 19).13 μg/ml.05 to P < . Intracellular concentration of β-Toco in male centenarians (0. P < . As a fat soluble vitamin.01) found in female centenarians compared to male centenarians.18 μg/ml.16 μg/ml.21 μg/ml.09 μg/ml.52 μg/ml. Despite adjustment.41 μg/ml for females (n = 91). Cases and controls were compared using Student’s t-test. 3.49 ± 0. n = 18). and both sexes combined (1. and eighties (n = 8. n = 72). Centenarians had significantly lower LPO levels than control subjects in their twenties (n = 8. n = 96) were significantly lower than in all younger age groups when both sexes combined were compared to younger age groups. female P < . females (2.37 ± 3. and both sexes combined (0. n = 18).51 ± 1. 22]. n = 91) showed similar trends as T-Toc. 3. females (9.09 ± 0. there 3. Intracellular concentration of γ-tocopherol in centenarian males (0.05) and female (P < . 1.00 μg/ml. Intracellular concentration of individual tocopherol subtypes (α-Toco.19 ± 1. n = 90) were significantly lower than septuagenarians with regard to the combined (P < . it reached significance versus only two groups— septuagenarian females (P < . where tocopherol concentrations were measured by high performance liquid chromatography (HPLC) [23].40 ± 0.93 ± 0. female centenarians (0. n = 72).58 ± 3.

76 (30)∗ 1.05).58 (4) 0.09 (8) 1. 20s 3.89 ± 2. P < .69 (30)∗∗∗ 16. 25].53 (8)∗∗ 3.17 ± 0.21 ± 0.60 (8)∗∗ 11.04 (8) 0.62 ± 1.27 (8)∗∗∗ 100s 7.21 ± 0.01.71 ± 3.01 ± 0.32.07 (5)∗ 13.79 ± 2. middle-aged. in septuagenarians there were some correlations between tocopherol levels and LPO: (1) a weakly positive correlation was found between plasma T-tocopherol and LPO (r = . P < .04 (8) 1.82 (17)∗ 16.24 (8)∗∗∗ 2.64 (30)∗∗ 15.31±11.46 (8) 13.23 ± 0.49 (8) 10.44 ± 1.07 ± 3.03 ± 0.45 (47)∗ 14.08 (17)∗ 0.42 (18) 1.10 ± 3. Discussion In 1956 Harman proposed the Free Radical Theory of aging [3].04 (4) 0. .91 ± 0.37 (5)∗ 15.69 (16)∗∗ 0.00 ± 0.51 (17) 1.28 (109) 1.20 ± 0.07 (18) 0.62 (3)∗∗∗ 12.001.79 (29)∗∗∗ 80s 2.62 (4) 10.56 ± 0.37 ± 0. 4.30 ± 1.34 (8)∗∗∗ 100s 1. Table 7 shows correlation indices between plasma tocopherol/tocopherol subfractions and LPO as well as between intracellular tocopherol and LPO in two age groups: centenarians and septuagenarians.05) and between intracellular α-tocopherol and LPO (r = −.01).18 ± 0. P < . nmol/ml.42 ± 3.64 (4)∗ 3.22 (4) 1. P < .59 (72) 1.88 (8)∗∗ 0.31 (19) 11.81 ± 3.21 (69) 0.28 ± 0.16 (47)∗∗ 1.32 (5)∗∗∗ 2.33 ± 3.17 ± 0.60 (4)∗∗ 10. He hypothesized that aging is partly due to cumulative oxidative damage.87 (8) 13.11 ± 0.28 (17)∗ 18.78 ± 2.67 ± 1.01 in α Toc.33.40 ± 0.32 (47)∗∗∗ 80s 9.37 ± 3. and between α-tocopherol and LPO (r = .14 ± 11.24 ± 12.50 (8) 1. ∗∗∗ P < .05.08 (16)∗∗∗ 70s 3.28 ± 0.23 ± 0.72 ± 1.46 (3) 2.23 ± 0. In centenarians.41 (91) 10.001.91 (8) 11.81 ± 11.82 ± 1.68 ± 3.05 (5) 0. ∗∗ P < .20 ± 0.58 ± 2.05 (8) 0. P < .17 ± 0. the literature shows that a progressive accumulation of oxidation-derived damage to cellular machinery is linked to senescence [2.52 (90) 8.63 (3) 11.93 ± 0.22 ± 0.70 (11)∗∗∗ 3.58 ± 3. ∗∗ P < 0.18 (30)∗∗ 0. (2) a weakly negative correlation was found between intracellular T-tocopherol and LPO (r = −.73 (16)∗∗∗ 70s 13.28 ± 3.41 (47)∗∗∗ 0.05 in total Toc.19 (87) 0. Age Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) 20s 11.80 (4)∗∗∗ 12. no significant correlations were found between plasma tocopherol nor tocopherol subfractions and LPO.95 ± 0.04 (16) 1.35 ± 3.51 ± 1.10 (19) 9. were no significant differences between centenarians and septuagenarians across age strata.03 ± 3. For example.74 ± 3. and older age groups (mean and SD).25 ± 0.33 (5) 1.90 ± 0.49 ± 0.34 ± 1.04 ± 0.13 (3) 0. However. and over the last four decades many studies have supported this view.01).69 ± 2.29.17 (3) 1.4 Current Gerontology and Geriatrics Research Table 1: Plasma lipid peroxide in young. separated by gender.98 ± 0.18 ± 0.40 (8) 1. Tables 5 and 6 show tocopherol: LPO ratios in plasma (Table 5) and intracellular (Table 6) compartments across age strata.01 ± 3.16 (139) Male (n) Female (n) Total (n) Significant difference between centenarians and particular age group: ∗ P < .20 ± 0.38 ± 8.05 ± 3. 22].05.15 ± 0. Significant difference between male and female centenarians: P < .04 (4) 0.35 (72) 9.81 (18)∗∗∗ 3.15 ± 7.39 ± 1.92 ± 0.31 ± 0.06 ± 1.16 ± 0.82 ± 3.70 (8)∗∗∗ 12.44 (16) 13.31 (8)∗∗∗ 30s 12. ∗∗∗ P < . No significant differences were found for either gender between the centenarians and controls in their seventies.58 ± 3.03 (4)∗∗ 9. LPO levels were measured using the TBA method [21.32 (110) α Toc β Toc γ Toc Total Toc Toc: Tocopherol.20 (8)∗ 0. Table 2: Mean plasma tocopherol (total and subtype) by age group (μg/ml).34.25 (8)∗∗∗ 30s 4.51 (30) 1.01.22 ± 0.79 (4) 3. Significant difference between centenarians and particular age group: ∗ P < .32 (91) 0.18 ± 0.

17 (30)∗ 0. some data suggest that βtocopherol might be a more effective antioxidant than αtocopherol.48 ± 0.00 ± 1. might do so by aging more slowly [27].91 ± 0.90 ± 0.80 ± 1. Since tocopherols are lipid soluble. correcting for different lipid levels across age strata was unrevealing.43 ± 0.76 (3)∗∗∗ 3.24 ± 0. The present work finds some support for this view.05 ± 0.08 ± 0.12 (8) 0..87 (3) 2.01 (8) 0.10 ± 0.06 (4) 0.19 (74) 0.57 (8)∗∗∗ 5 α Toc β Toc γ Toc Total Toc Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) 100s 1.05 ± 0.05.13 (8) 2.62 (16)∗∗∗ 70s 2.25 ± 0.95 ± 0. there is no clear indication from the present study that tocopherol and its subtypes (both plasma and intracellular) are leading biological factors in such a system. In addition.23 ± 0.39 (4)∗∗∗ 2.07 (8) 2.61 ± 0.35 ± 0.37 (5)∗ 3.01 (16) 0.19 ± 1.11 (8) 0. Significant difference centenarians and individual age groups: ∗ P < .01 (5) 0. ∗∗ P < 0. lipid peroxidation may be a key player for initiating and/or mediating aspects of the aging process.41 (8)∗∗∗ 3.91 ± 0.50 (4)∗∗∗ 2.00 (4) 0.35 ± 0.32 ± 0.01 (17)∗ 0.79 ± 0.64 (16)∗∗ 0.82 (8) 2.32 ± 0.08 (37) 0.84 (19) 2.02 (3) 0. Therefore.04 ± 0.42 (8)∗∗∗ 30s 2.02 (47)∗∗ 0. with the possible exception of intracellular β-tocopherol. are prime targets for this damage [26].05 ± 0. For example.24 ± 0.05 ± 0. some studies suggest that intracellular concentration of antioxidants might be more relevant than plasma levels since the source of most free radicals is intracellular mitochondria.35 ± 0. for slower aging. and drops off significantly by centenarian years. which are in close proximity to mitochondria.40 (8)∗∗ 0. the key source of endogenous free radicals.001.06 ± 0. in part.25 (17)∗∗∗ 2. and other cellular components.30 ± 1.79 ± 0.61 (8)∗ 0.Current Gerontology and Geriatrics Research Table 3: Mean intracellular (red blood cell) tocopherol levels by age strata (total and subtype) (μg/ml).30 (17)∗∗∗ 2. LDL.76 ± 0. As humans age this damage can be observed as a progressive increase in blood lipid peroxidation byproducts [26].51 ± 0.g.01 (8) 0. result in better overall protection against oxidative stress. and much damage occurs intracellularly—to DNA.31 ± 0. our past data show that Okinawan centenarians have significantly lower total cholesterol and cholesterol subfractions (e. in older persons. since blood tocopherol was lower in centenarians than in younger controls.04 ± 0.89 ± 1.00 (4) 0. Some work suggests that persons who live to exceptional ages. display artificially low blood tocopherol levels since it is mainly lipid bound. then protection against lipid peroxidation may be a biological advantage that accounts.05 ± 0.49 (4)∗∗ 2.13 (77) 1.31 ± 0. HDL) than elderly controls in their seventies [30].05 ± 0.10 (5) 0.22 (77) 2.07 (47) 0.09 (17) 0.47 ± 0. For example. Lipids.04 ± 0.04 (10) 0. .08 (4) 0. ∗∗∗ P < . Researchers in [28] found that increased β-tocopherol was associated with decreased risk for metabolic syndrome.50 ± 0. However. the major component of cell membranes.98 ± 0.01 (8) 0.16 (3) 0.35 (8)∗∗ 2. Nevertheless. cell membranes. theoretically. If this is the case.87 ± 0. tocopherol: lipid ratios might better reflect physiologic levels than blood tocopherol levels.89 ± 0.00 (19) 2.66 ± 0.02 (30)∗∗ 0.01.19 (96) Toc: Tocopherol.05 ± 0.18 (92) 1.15 (47)∗ 2.39 ± 0.67 (47)∗∗∗ 80s 2. This is consistent with a survivor effect where those with high blood LPO levels are selected out (by death) leaving a population enriched with low blood LPO. whether in plasma or intracellular compartments.16 (18) 0.27 ± 0. who generally have low blood lipids.15 ± 0. a life shortening prediabetic condition that increases oxidative stress. β-tocopherol is less likely to act as a free radical itself after quenching oxygen radicals than αtocopherol [9].35 (4) 2. such as centenarians.09 (96) 0.76 (30)∗∗∗ 2.56 ± 0. While plasma β-tocopherol did not appear protective. Some protective endogenous and/or exogenous antioxidant defenses may be responsible for this effect. a very long-lived population. The fact that centenarians had higher intracellular βtocopherol is interesting.92 ± 0. Researchers in [29] found that replacement of αtocopherol by β-tocopherol enhances resistance to oxidative stress in a cell culture study.75 (8) 2.33 ± 0.04 ± 0. it is also possible that very old persons.28 (5)∗ 2. We confirmed that plasma LPO level increases with age in Okinawans.46 ± 0.82 (30)∗∗∗ 2.62 (47)∗∗∗ 0.11 (16) 2.53 ± 0.35 ± 0.09 ± 0.31 ± 0.01 (8) 0.61 ± 0. Therefore. This increased stability could. 20s 2.05 ± 0.

072 ± 0.24 ± 2.013 ± 0.98 (30µ 0.71 ± 3.07 ± 0.07 ± 0.73 (11µ 0.18 ± 7.37 (8µ 30s 3.08 ± 0.252 (17µ 0.020 (17µ 0.07 ± 0.25 ± 0.30 (8µ 0.38 (8µ 3.017 (47µ 0. Septuagenarians (aged 70s) Male (n) 0.95 ± 13.17 ± 0.57 ± 11.06 ± 0.005 (54µ Total (n) 0.90 (8µ 3.015 ± 0.98 ± 1.02 (65) 0.058 (30µ 0.90 (30µ 0.33 ± 0.52 (17µ 0.014 ± 0.002 (54µ 0.007 ± 0.032 (16µ 0.14 (30) 0.30 ± 0.19 ± 0.044 (47µ 0.34 ± 3.17 (11µ 4.04 ± 2.61 (16µ 9.07 ± 0.23 ± 3.20 (29µ 0.03 (8µ 0. Table 5: Average plasma tocopherol fractions/LPO across age strata.03 ± 0.072 ± 0.017 (15µ 0.40 ± 1.09 (50µ 0.39 ± 4.01 ± 4.47 ± 12.94 8 0.049 ± 0.013 ± 0.86 (67µ 8.016 ± 0.04 (8µ 0.59 (67µ 0.017 (65) 0.32 (8µ 0.81 (47µ 0.07 (15µ 0.018 (50µ 0.63 ± 0.34 (5µ 4.25 ± 0.28 (5µ 5.88 ± 9.08 ± 0.54 (3µ 0.18 ± 7.10 ± 0.047 (47µ 0.008 ± 0.017 (17µ 0.09 ± 0.27 ± 0.006 ± 0.009 (55µ 0.019 ± 0.007 ± 0.049 ± 0.27 ± 0.050 ± 0.007 ± 0.023 (68µ 0.08 ± 0.82 (47µ 0.29 (15µ 9.70 (82µ 0.40 ± 1.10 (47µ 0.33 (29µ 4.36 ± 0.43 ± 14.89 (3µ 3.002 (70) 0.12 ± 15.003 (17µ 0.002 ± 0.283 (47µ 0.65 (8µ 3.31 ± 0.018 (16µ 0.06 (4µ 0.84 (29µ 80s 3.04 (16µ 0.007 ± 0.002 ± 0.29 ± 0.005 ± 0.07 ± 0.40 ± 1.17 ± 11.004 (50µ 0.36 ± 9.07 ± 13.016 ± 0.014 ± 0. Note: no significant differences between groups.037 (16µ 0.03 ± 0.24 (64µ 0.07 ± 0.32 ± 0.013 (30µ Total (n) 0.26 (79µ 0.87 (3µ 4.021 (84) 0.58 ± 14.032 (71µ 0.75 ± 3.036 (47µ 0.007 (16µ 0.001 (16µ 0.38 ± 2.46 ± 2.32 ± 0.67 ± 2.05 ± 0.075 ± 0.003 (30µ 0.07 ± 0.07 ± 0.54 ± 1.43 ± 3.008 (17µ 0.006 (16µ Female (n) 0.053 ± 0. Note: no significant differences between groups.11 (11µ 0.08 ± 0.18 (29µ 0.67 (18µ 4.02 (50µ 0.28 ± 0.006 (70µ T-Toc/Tc Plasma α-Toc/Tc T-Toc/Tc α-Toc/Tc Intracellular γ-Toc/Tc β-Toc/Tc T-Toc/HDL-C Plasma α-Toc/HDL-C γ-Toc/HDL-C T-Toc/HDL-C Intracellular α-Toc/HDL-C γ-Toc/HDL-C Tc: Total cholesterol.01 (4µ 3.12 (15µ 0.006 (16µ 0.22 (18µ 0.03 (17µ 0.26 (8µ 0.71 ± 4.09 (65) 0.002 ± 0.07 ± 0.052 ± 0.060 ± 0.68 ± 7.28 (3µ 0.12 ± 0.009 (71) 0.25 ± 0.37 (18µ 4.41 (8µ 0.049 ± 0.08 ± 0.007 ± 0.007 ± 0. .013 ± 0.69 (4µ 3.08 ± 0.02 (4µ 0.44 (8µ 100s 6.010 (47µ Centenarians (aged 100s) Male (n) 0.02 ± 2.98 (8µ 4.004 (47µ 0.45 (16µ 3.036 (30µ 0.41 ± 1.41 ± 0.35 ± 0.010 (17µ 0.83 (11µ 5.06 ± 0.017 (30µ 0.30 (8µ 3.009 (71) 0.033 ± 0.03 (5µ 0.16 (5µ 0.37 ± 0.46 (82µ Total Toc/LPO α Toc/LPO β Toc/LPO γ Toc/LPO Toc: Tocopherol.32 (4µ 0.016 (17µ 0.030 (71µ 0.08 (8µ 0.005 ± 0.010 (55µ 0.11 (85) 0.063 (30µ 0.62 (8µ 3.057 ± 0.015 ± 0.38 (4µ 3.012 ± 0.047 ± 0.13 (16µ 0.45 ± 13.10 (69µ 0.06 ± 1.003 (15µ 0. Toc: Tocopherol.027 ± 0.259 (30µ 0.55 (17µ 0.238 (30µ 0.006 (17µ Female (n) 0.22 (83µ 8.94 ± 14.059 ± 0. LPO: lipid peroxidase.267 (17µ 0.056 ± 0.002 ± 0.016 (47µ 0.75 ± 7.07 ± 0.013 ± 0.41 (16µ 70s 4. HDL-C: high density lipoprotein cholesterol.42 (16µ 0.004 (65) 0.058 ± 0.031 (55µ 0.25 ± 0.007 ± 0.007 ± 0.09 (4µ 3.47 (15µ 1.029 (55µ 0.13 (99µ 5.6 Current Gerontology and Geriatrics Research Table 4: Plasma and intracellular tocopherols adjusted by lipid subfraction.27 ± 0.17 (18µ 0.285 (47µ 0.33 ± 0.016 ± 0.03 ± 0.34 (4µ 0.02 (15µ 0. Plasma Toc Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) 20s 4.016 (30µ 0.002 ± 0.002 ± 0.

21 (8) 0. Centenarian LPO levels were lower than elderly controls (60–79 years) in that study as well but higher than young controls (aged 21–40 years). Long-chain omega-3 PUFAs decrease the production of inflammatory eicosanoids.02 (18) 0.60 (87) 1.80 ± 0.42 (8) 0.01 (8) 0.74 ± 0.20 (15) 0.35 (3) 0.01 ± 0.24 (34) 0.28 (4) 0.84±1.28 (8) 0.88 (5) 1. A larger study by the same research group also showed that LPO increased with age until centenarian years where a significant decrement occurred [32].74 ± 0.21 (68) 0.34 (8) 0.57 (16) 0.78 (29) 0. Overall.68 (8) 0.18 ± 0.04 0. We did not find any significant differences between age groups for tocopherol: cholesterol and tocopherol: LPO ratios in centenarians versus younger controls.34∗∗ T-Toc 0. Centenarians were found to have increased levels of omega3 polyunsaturated fatty acids (PUFAs) and reduced content of omega-6 PUFAs relative to younger controls. the literature on oxidative stress as a longevity factor in humans is sparse. Since mitochondria produce most of the oxidative stress in cells.58 ± 1.43 (11) 0.31 (5) 0.03 (29) 0.05 ± 1.55 (4) 0.16 (5) 1. Interestingly.21 (83) 7 Total Toc/LPO α Toc/LPO β Toc/LPO γ Toc/LPO Toc: Tocopherol. Some data from studies of Italian centenarians are in agreement with our LPO findings in Okinawan centenarians.00 (4) 0.92 ± 0. this finding was only significant in septuagenarians and not in centenarians.69 (71) 1.33∗∗ −0.02 ± 0. However.06 ± 0.10 (16) 70s 0.01 ± 0. Table 7: Correlation coefficient between tocopherol and plasma lipid peroxide.21 RBC tocopherol α-Toc β-Toc 0.95 ± 1.38 (8) 100s 1.02 ± 0.08 ± 0.01 (16) 0.99 ± 1.21 ± 1.21 ± 0.11 ± 0.65 (3) 1.68±0. cytokines. and reactive oxygen species by acting directly to inhibit arachidonic acid metabolism and acting indirectly to modify inflammatory gene expression [33].13 (11) 0. were lower in centenarians than in elderly control subjects (60–79 years of age) [31].11 ± 0.01 0. For example.09 ± 0. Intracellular Toc Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) Male (n) Female (n) Total (n) 20s 0.10 (8) 0.61 (4) 0. .00 ± 1.19 (29) 80s 0.91 ± 1.01 ± 0.11 ± 0. Susceptibility to peroxidation of the erythrocyte membranes (when challenged) was also lower in centenarians than in older controls [32]. LPO: lipid peroxidase. a study of 15 centenarians (3 males.09 ± 0.22 ± 0.55 (8) 0.01.21 (18) 0.40 ± 1.01 (11) 0. and if this truly represents a protective factor for survival it is unclear why centenarians would not also exhibit this finding.01 ± 0.86±0.06 (8) 30s 0.11 −0.12 ± 0.12 ± 1.75 ± 0.94 (18) 0.06 −0.32 (8) 0.79 ± 0.03 (8) 0.76 ± 0.11 ± 0.33 ± 1.01 ± 0.02 ± 0.88 ± 0.13 (4) 0.59 (16) 0.12 ± 0.03 (4) 0. More study of this issue is warranted.73 ± 0.11 ± 0.92 (16) 1.00 (18) 0.84 ± 0.84 ± 0. Plasma tocopherol α-Toc β-Toc 0.02 ± 0. 12 females) recruited from central Italy compared with equal numbers of controls (young.32∗ P < .03 0.01 ± 0.12 (16) 1.27 (4) 0. evaluated as MDA content.04 (3) 0.05.02 0.02 ± 0.09 ± 0. and this could help explain their exceptional longevity. less damage.04 −0.01 ± 0.60 ± 0. This suggests that centenarians might have mechanisms to keep oxidative stress at levels equivalent to persons who are decades younger.Current Gerontology and Geriatrics Research Table 6: Intracellular tocopherol: lipid peroxide ratios across age strata. ∗∗ P < .01 (8) 0.03 (8) 0.79 (8) 0.44 (71) 1.07 ± 1.89 (3) 0.36 (11) 0.67 ± 1. Note: no significant differences between groups.33 (8) 1. a weakly negative correlation was found between intracellular tocopherol (T-tocopherol and αtocopherol) and LPO in septuagenarians.11 Centenarians (n = 139) Septuagenarians (n = 61) ∗ T-Toc 0.36 (87) 0.89±0.22 (42) 0.03 (5) 0. middle aged and elderly) showed that blood LPO levels.01 −0.09 ± 0.86 ± 0.16 γ-Toc −0. higher intracellular levels of tocopherol should result in lower LPO levels and theoretically. Vitamin E was not measured in these studies but another potential mechanism was identified.29∗ −0.00 (4) 0.02 γ-Toc −0.01 ± 0.85 (29) 0.13 ± 0.02 (8) 0.10 ± 0.

Exceptional longevity has been linked to lower caloric intake. the possibility still exists that other factors correlated with vitamin E could have been responsible for the association.8 While there were tentative links established in the current study between oxidative stress and vitamin E in the Okinawans. ApoE null mice have lower serum apolipoprotein E and develop significant early atherosclerosis [45] but overexpression of catalase. a major antioxidant. cholesterol subtypes. the traditional healthy Okinawan diet. or membrane fluidity [54]. For example. . In the fruit fly (Drosophila melanogaster). if there is truly less ongoing oxidative damage in centenarians then the etiology is probably complex and involves interplay of genetic and environmental factors that operate over a lifetime. and humans [50]. high vitamin E consumption may merely reflect an overall dietary pattern that results in healthier aging. although few studies included exceptionally old persons [8. but do show alterations in healthspan [44]. Similar trends have been seen in studies of younger. work on Italian centenarians shows that they possess relatively high plasma vitamin E [55]. the two human genes that appear to have the strongest links to healthy aging and longevity. β-carotene. and was negatively correlated with vitamin C [11]. low plasma concentration of vitamin E and high concentration of lipid peroxide at baseline predicted risk of cardiovascular events over a 4-year follow-up [12]. rodents. including triglycerides. showed that plasma LPO was positively correlated with a great many cardiovascular risk factors. It is likely that several mechanisms account for low LPO at exceptional ages. aged 25–74. a clinical trial of vitamin E supplementation of up to 2. A combination of scientific approaches will be needed to tease out the important mechanisms. The current study found that females tended to have significantly higher tocopherol (total and α) levels than males. in a longitudinal study of healthy oldest-old (ages 80-plus). fibrinogen. the absence of CuZn superoxide dismutase. Interestingly. middle-aged. However. has 16. studies that focused on other measures of systemic defenses against oxidative stress have shown that centenarians exhibited higher red blood cell glutathione reductase and catalase activities. worms. young female adults [40]. and older persons. For example. A study of Polish centenarians also showed that centenarians had high vitamin E levels compared with healthy. and WBC count. This is markedly higher than the Japanese traditional diet with 6. For example. which could result in lower oxidative stress [40]. Indeed. females: 8 mg/d) [15]. increases sensitivity to oxidative damage and reduces lifespan by approximately 80% but genetic rescue of half the enzyme restores lifespan [42. While adjustment for vitamin C. 34–36]. there has been no causative link to longevity. Studies of Danish centenarians also found that glutathione reductase activity was higher in centenarian erythrocytes than in younger controls. Nevertheless. rodents. such dramatic effects are not seen in rodent models where mice with genetic alterations in antioxidant defenses typically show little alteration in lifespan. we were not able to strongly link vitamin Ederived tocopherols to reduced oxidative stress across all measures. which is a remarkable 190% of the Japan RDA. 14]. many epidemiologic studies show a protective association for vitamin E with age-related chronic diseases but support from interventional clinical trials has been lacking [56]. It is difficult to control for all such associations in epidemiologic work. Along the same line of thinking. Conversely. ApoE and FOXO3A [47–49] are both linked to oxidative stress. The literature is mixed with regard to gender differences. 43]. when clinical trials have been conducted with vitamin E on incidence and progression of age-related chronic diseases the bulk of the evidence is not supportive of an important protective effect [56]. Finally. with reports of higher plasma α-tocopherol in males [37] or females [38]. BMI.000 iu/day for 8 weeks was also not supportive of in vivo antioxidative effects. a cross-sectional epidemiologic study of over 700 men and women. Interestingly. Genes that influence oxidative stress might also be fertile areas for investigation. These might be fertile areas to search for relations with vitamin E. among other factors that might lead to lower oxidative stress [1. Most measures of vitamin E in this study also increased with age until the 70s and then dropped off. although genetic alterations of model organisms. including yeast. and serum lipids did not affect the relation. Moreover. This was also linked to healthy aging where centenarians with the highest cognitive and physical function tended to have the greatest enzyme activity [41]. such as second messenger molecular signaling [52] and/or other cardioprotective mechanisms [53]. and FOXO3A protects cells from oxidative stress [51] It is also possible that vitamin-E derived tocopherols may act through mechanisms that are not clearly linked to oxidative stress.6 mg a day of vitamin E. overexpression of antioxidative enzymes through knockout models or other means can dramatically increase lifespan. APOE genotype influences oxidative stress and inflammation in cell Current Gerontology and Geriatrics Research lines. The lack of robust support in the current study and the literature in general for a powerful effect of vitamin E against LPO does not mean that vitamin E is unimportant to healthy aging. an important antioxidative defense. more efficient metabolism. such as variants in HLA genes that may lead to less inflammation [57] and genetic variants in the FOXO3A gene with potentially pleiotropic mechanisms for reducing oxidative stress [48]. In fact. LPO was higher in those aged in their 20s. This study showed no change on three different indices of lipid peroxide (urinary 4-hydroxynonenal and 2 different isoprostanes) [39]. which is associated with a high prevalence of centenarians. have yielded conflicting data. 30s. and the possibility that vitamin E is simply correlated with another more active molecule(s) cannot be completely ruled out.3 mg a day and 72% of the RDA for Japan (RDAJ = males: 10 mg/d. appears to confer protection against early atherosclerosis [46]. However. and 70s and dropped off in the 80s and 100s. It is possible that measuring oxidative stress through TBA may not be the optimal method to assess vitamin E’s antioxidant effects. We have also found genetic factors that may be important. In addition. increased insulin sensitivity. and drosophila.

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