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Vitamin e supplementation and lifespan in model organisms

Contents lists available at Ageing Research Reviews Vitamin E supplementation and lifespan in model organisms I.M.A. Ernst , K. Pallauf , J.K. Bendall , L. Paulsen , S. Nikolai , P. Huebbe , T. Roeder , G. Rimbach a Institute of Human Nutrition and Food Science, Christian-Albrechts-University Kiel, Hermann-Rodewald-Straße 6-8, D-24118 Kiel, Germany b Zoological Institute, Zoophysiology II, Christian-Albrechts-University Kiel, Olshausenstraße 40, D-24098 Kiel, Germany c Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, OX39DU, UK We have conducted a comprehensive literature review regarding the effect of vitamin E on lifespan in Received 23 July 2012 model organisms including single-cell organisms, rotifers, Caenorhabditis elegans, Drosophila melanogaster Received in revised form 2 October 2012 and laboratory rodents. We searched Pubmed and ISI Web of knowledge for studies up to 2011 using the Accepted 4 October 2012 terms "tocopherols", "tocotrienols", "lifespan" and "longevity" in the above mentioned model organisms.
Available online 23 October 2012 Twenty-four studies were included in the final analysis. While some studies suggest an increase in life- span due to vitamin E, other studies did not observe any vitamin E-mediated changes in lifespan in model organisms. Furthermore there are several studies reporting a decrease in lifespan in response to vitamin E supplementation. Different outcomes between studies may be partly related to species-specific differ- ences, differences in vitamin E concentrations and the vitamin E congeners administered. The findings of our literature review suggest that there is no consistent beneficial effect of vitamin E on lifespan in model organisms which is consistent with reports in human intervention studies.
2012 Elsevier B.V. All rights reserved.
the lifespan of single cell organisms and rotifers, nematodes, flies, mice and rats.
The term vitamin E is used to describe a group of eight lipid soluble substances with a chromanol ring and a saturated (toco- pherols) or unsaturated (tocotrienols) carbon side chain (see 2. Vitamin E supplementation in different model
Depending on the methyl groups found at the chromanol groups these compounds are referred to as ␣-, ␤-, ␥- or ␦-tocopherols and tocotrienols (As a free radical 2.1. Single-celled organisms and rotifers scavenger and lipophilic molecule, vitamin E may protect the mem- branes from oxidative damage by reacting with fatty acid peroxides The effect of vitamin E on single-cell organisms and rotifers via electron transfer Additionally, vita- was examined in five studies min E may regulate gene expression ( Over the last few decades a possible influence of Of these studies, four reported vitamin E on longevity has been studied in animals and humans.
an increase in lifespan with vitamin E and one, on Saccharomyces However, it remains unclear whether this group of antioxidants cerevisiae (showed a reduction in lifespan. These can prolong or, on the contrary, decrease lifespan. In this review, we findings are summarized in summarize the studies on vitamin E supplementation and lifespan in model organisms of increasing biological complexity, thereby 2.1.1. Rotifer Philodina addressing the question if and to what extent vitamin E increases The first study to investigate the influence of vitamin E on the lifespan of rotifers was conducted by the rotifer Philodina. In this study, dl-␣-tocopherol at a concentration of 0.05 ␮l/ml (solubilized in Tween 80) was added ∗ Corresponding author. Tel.: +49 431 880 5312; fax: +49 431 880 2628.
to the medium in which the rotifers were grown. The rotifers were E-mail addresses: (I.M.A. Ernst), transferred to new medium every 24 h and checked for vitality.
(K. Pallauf), (J.K. Bendall), Vitamin E treatment significantly increased mean lifespan com- (L. Paulsen), (S. Nikolai), pared to both the solvent control and the non-solvent control (P. Huebbe), (T. Roeder), (G. Rimbach).
(by 1.9 days (10.2%) and 1.7 days (9.2%) respectively), whilst maxi- 1 These authors contributed equally to this review.
mum lifespan was unaffected. Furthermore, the average number of 1568-1637/$ – see front matter 2012 Elsevier B.V. All rights reserved.

I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 Fig. 1. Chemical structures of tocopherols and tocotrienols.
Vitamin E lifespan studies on single-cell organisms and rotifers in chronological order.
−7.5 days (n.s.) –, data is not available; n.s., not significant.
offspring per rotifer was significantly increased by 10% compared to both control groups.
Maximum clonal lifespan in days and fissions of P. tetraurelia supplemented with different amounts of ␣-tocopherol.
2.1.2. Asplanchna brightwelli Sawada and Enesco examined the effect of vitamin E on another rotifer, Asplanchna brightwelli. dl-␣-Tocopherol solubi- lifespan in fissions lized in Tween-80 was used at concentrations ranging between 5 and 100 ␮g/ml. They demonstrated that 25 ␮g/ml of tocopherol extended mean lifespan (±S.E.M.) of the rotifers from Differences are not statistically significant (p > 0.05) (modified from 5.5 days (±0.13) to 6.4 days (±0.17) compared to the control, whilst lower concentrations had little effect. Interestingly, the highest concentration used, 100 ␮g/ml, caused a reduction in life- lifespan, measured in days and fissions. The supplemented sub- span. Based on these initial results, they used ␣-tocopherol at groups demonstrated a bulk increase in maximum lifespan by 17.6% a concentration of 25 ␮g/ml in subsequent experiments aimed and in mean lifespan by 14.1% compared with controls (supplemen- at elucidating the exact timing of the effects. They solubilized tation 58.5 ± 16.6 vs. control 50.5 ± 10.6). Subsequent experiments 25 ␮g/ml ␣-tocopherol in either Tween-80 or ethanol and found investigated the impact of switching the organisms from control that the increase in mean lifespan was similar with both solvents.
to vitamin E (25 ␮g/ml) media early in life at days 0, 1, 9, 17 or By separating the rotifers into pre-reproductive, reproductive and 25. Only those subgroups transferred at day 9 showed a signif- post-reproductive periods, they found that lifespan was only signif- icant increase in mean lifespan in days and fissions. Those that icantly increased during the pre-reproductive period. The number were transferred to ␣-tocopherol-containing media after 9 days of of offspring was unaffected in this experiment ( clonal lifespan showed only minor, inconsistent effects on lifespan This study also evaluated the effects of higher concentrations of 2.1.3. Paramecium tetraurelia ␣-tocopherol (100 and 1000 ␮g/ml) on maximum clonal lifespan.
In 1988, Thomas and Nyberg were the first to investigate the An increase in the maximum lifespan was observed with increasing effects of vitamin E on the lifespan of a single-celled organism, doses of ␣-tocopherol, yet these data were non-significant. Paramecium tetraurelia. The effect of 25 ␮g/ml dl-␣-tocopherol was summarizes the results of this experiment.
examined in eight different genotypes, of which only one (that with Interestingly, however, when comparing controls to organisms the shortest mean lifespan) showed a significant increase in mean given 25 ␮g/ml of ␣-tocopherol and organisms given 100 ␮g/ml I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 to those given 1000 ␮g/ml of ␣-tocopherol, the subgroups that received the higher concentrations of ␣-tocopherol showed a Caenorhabditis briggsae ( slower increase in death rate despite a higher initial mortality, and Turbatrix aceti indicating that an adaptive process may have occurred. The same Vitamin E, with few exceptions, has been shown to extend the pattern was observed for fission rates. Furthermore 25 ␮g/ml of lifespan of nematodes (see One study showed that ␣- ␣-tocopherol increased the survival of non-dividing organisms tocopherol treatment increased both mean and maximum lifespan beyond their clonal lifespan from 1.05 days to 1.49 days when com- (whereas others only demonstrated pared to controls ( an effect on mean lifespan Minogue and Thomas provided further evidence of the effects of higher doses of vitamin E on P. tetraurelia. The authors or showed no effect at all ( observed that high concentrations of ␣-tocopherol (100, 1000 and 10,000 ␮g/ml) dose-dependently enhanced mean lifespan, despite 2.2.1. C. briggsae lower concentrations modestly reducing lifespan compared to Epstein and Gershon in 1972 were the first to investigate the controls with or without medium. 1000 ␮g/ml of ␣-tocopherol effects of vitamin E on aging in nematodes, specifically in C. briggsae.
extended mean lifespan by 126.5 fissions (49.5%) and 115 days ␣-Tocopheryl-quinone at 400 ␮g/ml had no effect on the length (151.3%) compared to controls (mean lifespan in days ± S.E.M.: of their reproductive period nor on the number of progeny. Con- supplementation 191 ± 16 vs. control 80 ± 3; mean lifespan in tinuous supplementation with 400 ␮g/ml ␣-tocopheryl-quinone fissions ± S.E.M.: supplementation 382 ± 4 vs. control 278.5 ± 11) increased the median lifespan by 11 days (31%) and the maxi- whilst 10,000 ␮g of ␣-tocopherol increased lifespan by 83.5 fissions mum lifespan by 13 days (23%) compared to medium and solvent (32.7%) and 216.5 days (234.9%) (mean lifespan in days ± S.E.M.: controls. Administering the ␣-tocopheryl-quinone on days 1, 10, supplementation 292.5 ± 8.5 vs. control 80 ± 3; mean lifespan in 20 or 30 revealed that only an early initiation of the treatment fissions ± S.E.M.: supplementation 339 ± 13 vs. control 278.5 ± 11).
prolonged median and maximum lifespan; starting treatment at Maximum lifespan was not reported. Minogue and Thomas also days 20 or 30 had no effect. The duration of ␣-tocopheryl-quinone found that the survival curves of P. tetraurelia supplemented with treatment correlated with the increase in the nematodes lifespan; 10 and 100 ␮g/ml of ␣-tocopherol were no different to controls, treating for 6 days after hatching prolonged median lifespan by displaying little mortality in the early phase of lifespan with a 5 days (16%) and maximum lifespan by 6 days (10%), treating for sudden and strong reduction in survival later in the lifespan. How- 10 days prolonged median lifespan by 11 days (31%) (supplemen- ever, organisms treated with 1000 ␮g/ml of ␣-tocopherol had a tation 46 ± 2 days vs. control 35 ± 2 days) and maximum lifespan by high mortality rate in the first 4 weeks with only 75% surviving.
14 days (25%) (supplementation 69 ± 4 days vs. control 56 ± 3 days).
Mortality in this group then slowed until survival dropped again ␣-Tocopheryl-quinone treatment was found to delay the accumu- in the late stages of their lifespan. Those organisms administered lation of lipofuscin, suggesting that it has antioxidant properties 10,000 ␮g/ml of ␣-tocopherol demonstrated a strong initial decline in survival such that only ∼50% survived until 5 weeks. Survival then plateau'd until 15 weeks when the death rate slowly increased again. Death rates confirmed the survival curves with the high dose Following on from the work of Epstein and Gershon, Kahn and treatments showing a consistently elevated death rate indicating a Enesco found that dl-␣-tocopherol at a concentration of 100 ␮g/ml cytotoxic effect of ␣-tocopherol ( significantly increased the mean lifespan (±S.D.) of the nema- tode T. aceti by 15.3 days (33.7%) (supplementation 60.7 ± 30.6 days 2.1.4. S. cerevisiae vs. control 45.4 ± 29.5 days) and increased the maximum lifespan More recently, the effect of ␣- by 8 days (7%) compared to the control. This increase in lifespan tocopherol on the lifespan of the baker's yeast, S. cerevisiae. The occurred in the early phase, before day 30, and in the late phase, organisms of the K6001 strain were grown in the linear phase in after day 72. In subsequent experiments, nematodes were initially glucose medium with vitamin E concentrations ranging between grown in treatment or control medium and then transferred to 20 and 150 ␮M. They found that ␣-tocopherol dose-dependently treatment or control medium, yielding four supplementation pat- decreased replicative lifespan (estimated by measuring the opti- terns (control–treatment, control–control, treatment–control and cal density of the medium). However, cell viability was unaltered treatment–treatment). The results demonstrated that early treat- by these ␣-tocopherol concentrations. To elucidate the molecu- ment with ␣-tocopherol (i.e. within the first 24 h after hatching) lar properties of ␣-tocopherol responsible for the observed effects significantly increased mean lifespan by up to 46.2%. Transferring they used ␣-tocopherol acetate, which lacks antioxidant activity, the nematodes 96 h after hatching had no significant effect on life- 2,2,5,7,8-pentamethyl-6-hydroxychroman (PMC) and trolox, two span. Together, this study indicates that ␣-tocopherol exerts its synthetic analogs of vitamin E which lack the phytyl tail. Only positive effects on nematodes in the early phase of their lifespan PMC decreased the replicative lifespan in the same dose-dependent manner as ␣-tocopherol. However, PMC also decreased cell viabil- ity indicating a toxic effect. Thus, Lam et al. concluded that both 2.2.3. C. elegans the antioxidant capacity and lipid solubility of ␣-tocopherol are Influence of time and dose of ˛-tocopherol supplemen- responsible for its effects on S. cerevisiae. In contradiction to its tation. Zuckermann and Geist evaluated whether there is an antioxidant activity, vitamin E was found to increase ROS pro- age-dependent effect of ␣-tocopherol on lifespan. Parental C. ele- duction and thus oxidative stress when administered for 20 h.
gans were grown in an ␣-tocopherol (200 ␮g/ml)-supplemented or Combining ␣-tocopherol with coenzyme Q10, another antioxidant solvent control medium and newly born nematodes transferred to which may potentially restore ␣-tocopherol, was also unsuccessful; either an ␣-tocopherol or control medium at hatch or day four. The replicative lifespan was similarly decreased maximum lifespan and the time point at which 50% of the worms were still alive were measured. These survival rates showed that there seems to be no carryover effect from the paternal genera- tion to the offspring as the progeny from vitamin E supplemented The most commonly used nematodes to test the responses to and control parents showed no difference regarding lifespan. How- tocopherols and tocotrienols are Caenorhabditis elegans ( ever, if the nematodes hatched from egg masses and stayed in I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 Vitamin E lifespan studies on nematodes in chronological order.
Form of vitamin E Caenorhabditis briggsae ␣-Tocopheryl quinone Caenorhabditis elegans Caenorhabditis elegans Caenorhabditis elegans ␣-Tocopherol acetate Tocotrienol mix.
Caenorhabditis elegans −1.8 days (n.s.) ␣-toc + ␥-toc –, data is not available; n.s., not significant; #, data are given as median.
vitamin E supplemented medium their lifespan increased by 7 days compared to the solvent control. At concentrations of 200 and compared to those without vitamin E supplementation (supple- 400 ␮g/ml, dl-␣-tocopherol significantly decreased the number of mentation 54 days vs. control 47 days). Later supplementation did offspring per animal by 23–30% and significantly delayed the onset not significantly affect the 50% survival rate but increased the maxi- of their reproductive period by 19–28%. The authors concluded mum lifespan (supplementation 74 days vs. control 66 days). These that higher doses of vitamin E can lead to growth retardation or results suggest that ␣-tocopherol exerts its effects in the early developmental delay stages of the lifespan of nematodes. Zuckermann and Geist also demonstrated that high concentrations of ␣-tocopherol (400 ␮g/ml and 800 ␮g/ml) had detrimental effects on T. aceti, reducing Supplementation with tocopherol and tocotrienols. To com- their size and the number of offspring compared to controls and pare the influence of tocotrienols and tocopherols on the lifespan lower concentrations of ␣-tocopherol (200 ␮g/ml). These results of C. elegans, Adachi and Ishii used dl-␣-tocopherol acetate and again suggest that ␣-tocopherol is toxic at higher concentrations an extract of palm oil (referred to as "tocotrienol mixture") con- taining 95% of vitamin E composed of 22% ␣-tocopherol, 24% ␣-tocotrienol, 37% ␥-tocotrienol and 12% ␦-tocotrienol. When given in the adult stage, the tocotrienol mixture at doses of 8 Effects of ˛-tocopherol on development and aging. Harring- and 80 ␮g/ml medium significantly increased the mean lifespan ton and Harley examined in more detail the distinct effects of of C. elegans by 1.5 days (8.7%) and 3.2 days (19.8%) (supplemen- ␣-tocopherol on development and aging in C. elegans. The addition tation 18.7 ± 1.9 and 20.6 ± 1.6 days vs. control 17.2 ± 1.8 days), of 200 ␮g/ml dl-␣-tocopherol after hatching (levels were depleted respectively, while maximum lifespan was unaffected. In contrast, after 3 days) increased maximum lifespan by 5 days (17%) (supple- 80 ␮g/ml of ␣-tocopherol acetate did not significantly alter life- mentation 34 days vs. control 29 days), median lifespan by 3 days span (The tocotrienol mixture (at 80 ␮g/ml) (16.6%) (supplementation 21 ± 1 days vs. control 18 ± 2 days) and significantly decreased the levels of carbonylated proteins by one mean lifespan by 4 days (20%) (supplementation 24 ± 1 days vs.
third in 15 day old animals, indicating that the mixture has antiox- control 27 ± 1 days), resulting in an overall significant increase in idant properties. The tocotrienol mixture (80 ␮g/ml) was also able the lifespan of C. elegans by 17% compared to the solvent control.
to abolish the significant reduction in lifespan caused by irradia- Continuous administration of dl-␣-tocopherol increased lifespan tion with ultraviolet light when given after the irradiation, whereas by 22%. Administration of ␣-tocopherol at 100 and 400 ␮g/ml ␣-tocopherol acetate (80 ␮g/ml) offered only minimal protection slightly, but not significantly, increased the nematodes lifespan which was non-significant. Furthermore, when treatment was by 9% and 4%, respectively. They found that when 200 ␮g/ml ␣- initiated before the irradiation insult, the tocotrienol mixture sig- tocopherol was administered to the nematodes from day 4 of life nificantly extended the lifespan by 2.1 days (12.1%) compared to until death, mean lifespan was significantly increased from 18 untreated, non-irradiated controls This to 21 days and maximum lifespan increased from 29 to 31 days is in accordance with a study showing that the lifespan increased I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 in C. elegans that were fed ␥-cyclodextrin tocotrienol complexes exogenous antioxidants may cause a compensatory depression of Complexation with ␥-cyclodextrin has been endogenous defenses. On the other hand, ␣-tocopherol treatment shown to enhance the absorption of lipid-soluble substances and did not alter catalase activity at both concentrations. The glu- may be used as a strategy to improve tocotrienol bioavailability tathione content of flies supplemented with both concentrations of ␣-tocopherol was also not statistically different from controls.
Hydrogen peroxide levels were dose-dependently increased by ␣- Wild-type and mev-1 mutant. Another study investigating tocopherol, reaching statistical significance at 2% ␣-tocopherol.
the effects of vitamin E on longevity in nematodes was conducted The appearance of fluorescent material (e.g. lipofuscin) which is by Ishii et al. in 2004. They treated wild-type C. elegans and the believed to accumulate in the aging organism upon free-radical mev-1 mutant that has increased superoxide production and is induced damage was not affected by the ␣-tocopherol treatment highly susceptible to oxidative damage, with Coenzyme Q10 and ␣- tocopherol. Mev-1 encodes a succinate dehydrogenase cytochrome b subunit. The mev-1 mutant has a defective electron transport in 2.3.2. Z. paravittiger complex II and is therefore characterized by an increased super- ␣-Tocopherol was administered to male and female fruit oxide production and is highly susceptible to oxidative damage.
flies of the species Z. paravittiger at concentrations ranging A mutation in the succinate dehydrogenase cytochrome b causes between 1 and 50 ␮g/ml of medium. On the one hand, median oxidative stress and aging in nematodes ( and maximum lifespan were significantly increased by ␣- ␣-Tocopherol (400 ␮g/ml) significantly increased the lifespan of tocopherol supplementation at concentrations of 1 ␮g/ml (median wild-type nematodes by 11% compared to untreated controls, yet lifespan mean ± S.D. male/female in days, 37.4 ± 0.1/43.3 ± 0.2; the lifespan of the mev-1 mutant remained unaltered. However, maximum lifespan ± S.D., 83.3 ± 1.2/85.0 ± 1.0), 5 ␮g/ml (median they found that, unlike Coenzyme Q10, vitamin E failed to diminish lifespan mean ± S.D. male/female in days, 46.9 ± 0.3/48.8 ± 0.5; levels of superoxide anion production in both wild-type nematodes maximum lifespan, 88.7 ± 1.2/99.3 ± 1.2) and 10 ␮g/ml (median and the mev-1 mutants ( lifespan mean ± S.D. male/female in days, 43.3 ± 0.7/46.4 ± 0.4; maximum lifespan, 85.7 ± 1.5/94.3 ± 1.5) in comparison to the Influence of ˛- and -tocopherol. Zou et al. studied the control (median lifespan mean ± S.D. male/female in days, effects of 20 and 200 ␮g/ml ␣-tocopherol or ␥-tocopherol on 35.1 ± 0.7/41.7 ± 0.1; maximum lifespan, 76.7 ± 1.2/82.0 ± 2.0). On the sterilized C. elegans mutant, fem-1, in adulthood. Their the other hand, ␣-tocopherol at concentrations of 25 and 50 ␮g/ml findings revealed opposing effects of the two tocopherols on life- decreased median and maximum lifespan by 33.7–54% and span. 200 ␮g/ml ␣-tocopherol marginally and non-significantly 16.1–35.5%, respectively (median lifespan mean ± S.D. male/female decreased mean lifespan and did not affect maximum lifespan. Con- in days, 23.3 ± 0.2/23.8 ± 0.3 and 16.8 ± 0.1/19.2 ± 0.2; maximum trastingly, ␥-tocopherol significantly extended mean lifespan to lifespan, 64.3 ± 0.6/65.0 ± 1 and 50.3 ± 1.2/53.7 ± 2.3). Supplemen- 14.7 days (16.7%) at 20 ␮g/ml and to 15.2 days (20.6%) at 200 ␮g/ml tation of ␣-tocopherol at 5 ␮g/ml decreased TBARS levels in fly compared to controls with a mean lifespan of 12.6 days. A combined homogenates at all ages, measured at 7-day intervals during a administration of ␣- and ␥-tocopherol in equal proportions at 20 period of 43 days starting from day 1. Furthermore, this concen- and 200 ␮g/ml did not significantly affect the lifespan of C. elegans.
tration of ␣-tocopherol ameliorated the age-dependent decrease The authors hypothesize that this might be due to ␣-tocopherol in the activity of the antioxidant enzymes catalase and peroxidase negating the positive effects of ␥-tocopherol ( 2.3.3. D. melanogaster Miquel et al. fed ∼3000 adult male flies of the species D.
The available data relating to the effects of vitamin E on the melanogaster a medium containing 0.06%, 0.12% or 0.25% ␣- lifespan of flies originates from five studies, of which four were con- tocopherol acetate. All three concentrations resulted in a significant ducted in Drosophila melanogaster increase in the flies' lifespan with the highest dose having the largest effect, increasing the mean and maximum lifespan by 8–15% lifespan in the fruit fly Zaprionus paravit- and by 12% compared to controls, respectively ( tiger and examined the effects on the Mexican Driver and Georgeou supplemented male flies with vitamin E fruit fly, Anastrepha ludens. In addition, the effects of ␣-tocopherol solubilized in ethyl acetate at concentrations of 3, 20, 100 and on the housefly Musca domestica were tested in a study by 200 ␮g/ml. The lifespan of control flies was 79 days (±6) whilst that main results of these studies are summarized in of flies administered 3, 20, and 200 ␮g/ml vitamin E was 86 (±6), 92 (±6) and 76 days (±2), respectively. As such, only the 20 ␮g/ml dose of vitamin E significantly elevated lifespan compared to con- 2.3.1. M. domestica trols. When given in conjunction with paraquat, a chemical that Sohal et al. fed flies sucrose containing 0.5% and 2% ␣- acts as a redox cycler and generates a superoxide anion radical tocopherol. The lower dose of ␣-tocopherol did not alter mean when metabolized in mitochondria, vitamin E at a concentration lifespan, whereas the higher dose significantly decreased lifespan of 200 ␮g/ml was able to extend lifespan and abolish the detri- by 5.4 days (26.1%) (supplementation 15.3 ± 4.2 days vs. control mental effects of paraquat. When flies were administered vitamin 20.7 ± 5.9 days). The metabolic rate, measured as oxygen consump- E at a concentration of 250 ␮l/ml for the first 6 weeks of life, their tion per time per weight of flies, was not affected by the treatment lifespan significantly decreased by 12.6 days (13.6%; supplemen- at either concentration. However, SOD activity was significantly tation 11.6 ± 0.31 vs. control 13.4 ± 0.3). Furthermore, the authors decreased in flies given 2% ␣-tocopherol at 6, 9 and 12 days of age found that vitamin E supplementation altered the circadian rhythm by between 20.3% and 24.9% compared to controls. Interestingly, of flies, causing a significantly different pattern and length of their the SOD activity of ␣-tocopherol-treated flies remained almost diurnal activity cycle when the lighting conditions were changed constant with age, while SOD activity in control flies increased from a 12 h dark, 12 h light cycle to continuous light ( from days 3 to 9 then slightly decreased on day 12. This indi- cates an age-related variation in SOD activity that is abolished Zou et al. investigated potential sex-specific differences in by ␣-tocopherol. The authors suggest that the administration of responses to ␣- and/or ␥-tocopherol at concentrations of 20, 100 or I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 Vitamin E lifespan studies on flies in chronological order.
−11.8/17.9 d. # −12.3/17 d.
−18.3/22.5 d. # −26.3/28.3 d.
0.005, 0.05, 0.5, –, data is not available; n.s., not significant; d, days; # data are given as median.
200 ␮g/ml in canton-S wild-type flies of the species D. melanogaster.
At 100 ␮g/ml, ␣-tocopherol modestly, yet significantly, increased the mean lifespan of female flies by 1.7% but had no affect on males.
As vertebrates and mammals, rodents are far more complex In contrast, the same dose of ␥-tocopherol as well as the two highest organisms than the others included so far in this review. A number doses of ␣- and ␥-tocopherol significantly reduced the mean life- of studies have been conducted in rodents to elucidate the effects span of female flies by 1.3 days (9.9%), 1.6 days (6.9%) and 2.9 days of vitamin E on lifespan; one in rats and seven (12.5%), respectively. The authors also reported that 100 ␮g/ml of ␣- or ␥-tocopherol did not significantly affect the lifespan of flies of the species A. ludens, with mean lifespan even slightly decreasing The main results of these eight studies are discussed below and summarized in Bahadorani et al. examined the effects of ␣-tocopherol in male SOD 1-deficient and wild-type D. melanogaster both under normal and elevated oxygen partial pressures. Food intake was found to be Lipman et al. investigated whether initiating antioxidant unaltered by treatment compared to controls. ␣-Tocopherol was supplementation during the late stage of a rodent's life is bene- tested under normal oxygen conditions at concentrations of 0.005, ficial in terms of longevity. Eighteen month old mice were given 0.05, 0.5, 5.0 and 25.0 IU/ml and was not found to significantly alter acetate at a concentration of 500 ␮g/g or a control dl-␣-tocopherol longevity. In addition to the lifespan extension in SOD 1-deficient diet containing 30 ␮g/g of vitamin E. They found that the vitamin flies, ␣-tocopherol significantly increased the antioxidant capac- E group showed an increase in bodyweight of 0.07 mg/kg day−1 ity of these animals, measured as trolox equivalents, by about 32% (based on the average food intake of the mice). However, whilst compared to the control ( serum levels of ␣-tocopherol were significantly higher in supple- Taken together, the studies examining the effects of ␣- mented mice, this did not lead to an improvement in longevity tocopherol in flies are inconsistent and do not show a uniform effect of vitamin E in these insects. Two studies reported a decrease in the Selman et al. induced oxidative stress in C57BL/6 mice by lifespan of flies supplemented with vitamin E decreasing room temperature (7 ◦C). Four month old male and whilst Zou et al. found no significant effect of female mice were supplemented with ␣-tocopherol at either vitamin E on the lifespan of A. ludens. Similarly, 22 ␮g/g or 550 ␮g/g. Supplementation had no effect on the rate our own experiments showed no significant effects on compared to controls but significantly increased both the median wild-type Drosophila. Both Driver and Georgeou as well as Kakkar and maximum lifespan in both sexes of mice. Median lifespan et al. observed differing effects on lifespan according to the dose of of ␣-tocopherol-supplemented mice was increased from 682 to 785 days (15.1%) compared to the control. Maximum lifespan, I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 Vitamin E lifespan studies on rodents in chronological order.
Rat (Wistar, male) –, data is not available; n.s., not significant; #, data are given as median.
determined as the age of the oldest 10% in each cohort, was signif- a higher tendency than the LAF1 strain. The mice were supple- icantly increased from 834 to 945 days (5.7%) in the ␣-tocopherol mented with 2500 ␮g/g dl-␣-tocopherol starting at 5 weeks of group compared to the control. The content of ␣-tocopherol in the age. Maximum longevity in ␣-tocopherol-supplemented mice of liver was significantly increased in supplemented animals but, in both strains was not significantly altered compared to control ani- accordance with the findings from below), mals. However, there was a significant increase in mean lifespan the levels of TBARS and the amount of oxidative damage to DNA of mice administered dl-␣-tocopherol compared to the control, were not affected by the higher amount of ␣-tocopherol. Addition- mainly caused by a decreased death rate prior to 24 month of age.
ally, decreasing the temperature in this experimental setting could ␣-Tocopherol treatment also decreased the number of fatal tumors also have induced incidents other than oxidative stress.
by 33.3% compared to the control. Furthermore, the predisposition Macroarray analysis revealed that the expression of several of the CH3H/He strain to develop more tumors was abolished in the hepatic genes was elevated in ␣-tocopherol-treated animals, supplemented subgroup. Furthermore, the content of lipofuscin in including seven genes encoding cytochrome p450 enzymes and the murine heart muscles was decreased by ␣-tocopherol by 28% genes encoding enzymes associated with phase II detoxification.
in CH3H/He mice and by 36% in LAF1 mice compared to the respec- However, Selman et al. found no significant increase in the expres- tive controls, indicating an antioxidant effect of dl-␣-tocopherol sion of genes encoding enzymes involved in cellular DNA repair or in these mice at the high concentration of 2500 ␮g/g ( antioxidant defense, such as SOD and catalase Ledvina and Hodanova conducted experiments in female mice Morley and Trainer evaluated the effects of supplementing with of the C3 strain. ␣-Tocopherol acetate solubilized in 1 ml of ether vitamin E straight after conception in Balb/c mice. Although serum and 1 ml of ethanol was added to the diet at a concentration of concentrations of vitamin E increased dose dependently with 20, 4.4 mg/g. The diet also contained 13.6 mg/g of sunflower oil. A sec- 400 and 4000 ␮g/g of vitamin E supplementation, the median life- ond experimental subgroup was fed on a diet containing sunflower span values did not significantly change with different vitamin E oil with an approximately equal iodine number of 127–136, at a concentrations or differ from controls (804, 830 and 802 days for concentration of 12.0 mg/g and solubilized in the same manner as female offspring supplemented with 20, 400 and 4000 ␮g of vita- the ␣-tocopherol diet. Animals commenced these diets at 46 days min E per g of food, respectively) ( of age. Food intake and body weight were significantly altered by Another study involved continuously supplementing adult CD- the treatments. Up to day 130, the mice ingested about 15.4 mg of 1/UCadiz mice with 5000 ␮g/g dl-␣-tocopherol from 28 weeks of ␣-tocopherol acetate, dropping to 13.6 mg from day 131 onwards age. The mice were monitored for their lifespan, neuromuscu- due to decreased food consumption. Mean and maximum lifespan lar and cognitive performance (tightrope and maze tests). The were higher in the ␣-tocopherol supplemented animals compared control diet contained 29 ␮g/g of dl-␣-tocopherol. Median and to control subgroups, yet this did not reach significance. Mean and maximum lifespan of supplemented male mice increased signif- maximum lifespan for the ␣-tocopherol supplemented subgroup, icantly from 61 ± 4 to 85 ± 4 weeks (39.3%) and from 116 ± 4 to the sunflower oil subgroup and the control were 704.2 ± 209 and 136 ± 4 weeks (17.2%), respectively. Median and maximum lifespan 1200 days, 620.4 ± 217.2 and 1078 days as well as 690.4 ± 168.1 and of female mice also increased from 78 ± 4 to 88 ± 5 weeks (12.8%) 933 days, respectively ( and 148 ± 4 to 155 ± 4 weeks (6.9%), respectively, but these changes A comparative approach on the effects of vitamin E on the life- were not significant. Furthermore, ␣-tocopherol-supplemented span of two strains of mice, the CH3H/He and LAF1 strains, was male mice demonstrated significantly enhanced neuromuscular taken by Blackett and Hall. These two strains differ in their pre- and cognitive performance at 50 and 76 weeks of age. The levels disposition for tumor development; the CH3H/He strain having of protein carbonylation products and TBARS in the liver and brain I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 were significantly decreased in ␣-tocopherol-supplemented mice highlights that vitamin E has inconsistent effects on longevity in at 76 weeks of age. ␣-Tocopherol also improved the age-associated single-celled organisms, rotifers, nematodes, flies and rodents.
reduction in activity of several protective enzymes, including nitric In accordance with the studies in model organisms described oxide synthase and SOD, in aging mice herein, studies in humans have yielded similarly inconsistent Hsieh and Lin supplemented MRL/lpr mice that suffer from an results regarding the beneficial effects of vitamin E, with ran- autoimmune disease and are susceptible to die within the first domized clinical trials reporting positive, negative and no effect 6 month of age with all-rac-␣-tocopherol acetate at concentrations depending on the outcome measured of 250, 375, and 500 ␮g/g. Control food contained 50 ␮g/g all-rac-␣- tocopherol acetate. ␣-Tocopherol supplementation had no effect on Because of its properties as a lipid-soluble feeding behavior and body weight of mice. They found that mice fed antioxidant and membrane protector, vitamin E was assumed 250 ␮g/g of all-rac-␣-tocopherol acetate lived significantly longer to ameliorate or prevent arteriosclerosis and thereby promote than mice supplemented with 500 ␮g/g all-rac-␣-tocopherol healthy aging. However, many well-designed randomized placebo- acetate (213 ± 76 days vs. 157 ± 49 days, respectively), and also controlled studies with sufficient power to detect clinical events, longer than control animals (177 ± 45 days) and those fed 375 ␮g/g such as HOPE, GISSI and PPP, have demonstrated a null effect of all-rac-␣-tocopherol acetate (162 ± 57 days). The higher doses of vitamin E in the treatment or prevention of coronary heart dis- all-rac-␣-tocopherol acetate led to significantly increased lev- els of the vitamin E in the liver, kidney and plasma but did However, two secondary prevention studies, CHAOS not reduce the levels of TBARS in these tissues ( and SPACE, suggest that vitamin E supplementation may be benefi- cial to coronary artery disease in certain sub-populations, although these studies were small with relatively short follow up ( In the Women's Health Study on vitamin E prevention of cardiovascular disease it was shown that Porta et al. studied the effects of dl-␣-tocopherol on the lifespan in spite of slightly decreasing cardiovascular mortality, vitamin E of male rats that were fed a diet enriched with 15% of either coconut supplementation could not lower total mortality oil (rich in saturated fatty acids), safflower oil (rich in unsaturated A large meta-analysis by comes to the con- fatty acids) or both oils combined from weaning.
clusion that vitamin E supplementation at high doses may elevate was added at a concentration of either 20 ␮g/g or 2000 ␮g/g but, the all-cause mortality. However, whilst the authors state that the due to the different amounts of vitamin E in the oils, the final con- high-dose trials were often carried out in patients with chronic centration was increased by 0.7 ␮g/g in the coconut oil diet, 5.2 ␮g/g diseases thereby making the analysis of the mortality data more in the safflower oil diet and by 3.4 ␮g/g in the oil combination complicated, a more recent meta-analysis concludes that vitamin E diet. Rats fed on the coconut oil-containing diet had significantly supplementation including high doses does not affect overall mor- reduced body weights soon after initiation of the diets. The mean tality The inconsistent results from large and and maximum lifespan of rats were not significantly affected by smaller scale human studies investigating the potential benefits of the different amounts of unsaturated fatty acids in the diets or by vitamin E supplementation clearly warrant the studies in model dl-␣-tocopherol supplementation. The 50% survival time (the day organisms in which confounding factors can be much more easily at which only 50% of a subgroup was still alive) was significantly controlled. Yet this review highlights that the discrepant results increased in the group receiving 2000 ␮g/g of dl-␣-tocopherol and prevail in studies using model organisms.
safflower oil compared to all other experimental subgroups and the These inconsistencies are likely to be attributable to a number control (median lifespan in days ± S.E.M. 594.7 ± 35.6 vs. control of factors. For example, there may be species–species differences 600.1 ± 30.6; mean lifespan ± S.E.M. 739.5 ± 34.1 vs. 724.7 ± 29.3; and the complexity of the model organism may be an important maximum lifespan ± S.E.M. 1013 ± 50.0 vs. 1037 ± 63.1). This bene- determinant of the function of vitamin E. However, a number of ficial effect was related to a delay in the onset, as well as a reduction distinct studies in the same species, including rodents and humans, in the incidence, of malignant neoplasms. The 50% survival time have reported contradictory results. The dose of vitamin E used in was also increased in rats fed on the combined oil diet supple- the studies differs greatly and many studies have shown a ben- mented with 20 ␮g/g dl-␣-tocopherol compared to the subgroups eficial effect of vitamin E at lower concentrations with higher supplemented with the same concentration of vitamin E but in dif- doses exhibiting adverse effects on lifespan ( ferent oils This indicates that the amount of unsaturated fatty acids in the oils may influence longevity.
Taken together, these studies in rodents show inconsistent Unfortunately, when using non-mammalian model orga- effects of vitamin E on longevity. Whilst three studies demonstrated nisms it is difficult to categorize the amounts used according to that vitamin E supplementation improves lifespan high and low doses because of a lack of daily dose recommendations making it difficult to deduce a dose-dependent effect of vitamin E failed to show significant lifespan effects but did reveal a signifi- on lifespan in flies and worms. Nevertheless, very high vitamin E cant increase in the time at which 50% animals were still alive ( concentrations have been used in many human studies which may Another study found divergent effects with different account for the lack of beneficial effect observed doses of vitamin E with a low concentration increasing lifespan and a higher concentration reducing it Three other studies found no significant effect of vitamin E administra- 3.1. Vitamin E as an antioxidant tion on longevity ( Deducing a possibly life-prolonging effect of vitamin E because of its antioxidant properties seems to have been a too rapid conclu- sion. Recently we have shown that in rodents, both vitamin E in the liver and biomarkers of oxidative stress increased with age, argu- The potential benefits of vitamin E on health and lifespan have ing against the hypothesis that a higher vitamin E status in older been intensely investigated and this review article focuses on organisms could attenuate oxidative damage ( the studies carried out in model organisms. This appraisal clearly Additionally, although oxidative stress accompanies the aging I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 process it is not necessarily its underlying cause and promoting the cells which could explain the different findings in vitamin E tri- organism's stress resistance rather than simply lowering ROS levels als on cardiovascular disease. On the one hand, seems to be the better strategy to slow down aging ( describe that ␥-tocopherol, in contrast to ␣-tocopherol, decreased Schulz et al. demonstrated that increased mitochondrial the synthesis of pro-inflammatory prostaglandin E2 by inhibi- ROS formation, as a consequence of reduced glucose availability, ting the cyclooxigenase 2 (COX-2). On the other hand, Bernikovs induces catalase activity and enhances oxidative stress resistance et al. found ␣-tocopherol as inhibiting inflammation by regulat- in C. elegans. Their results provide evidence for the mitochondrial ing endothelial cell signals during leukocyte recruitment. At a hormesis (or mitohormesis) theory of aging, which leads to an 10% ␥-tocopherol/␣-tocopherol ratio which is similar to the con- increase in overall life expectancy. Indeed, they showed that treat- centrations physiologically found in humans, ␥-tocopherol could ment of nematodes with various antioxidants and vitamins had abolish this anti-inflammatory effect ( the unexpected effect of decreasing lifespan Dietary vitamin E sources contain mostly ␣- and ␥-tocopherols Consistent with a counteracting role in ROS-induced hormesis, with ␥-tocopherol being more present in US-American diets than the antioxidant vitamin E prevented the health-promoting effects in European diets In the body, tocopherol of exercise in young men (It is well known is transported from the liver via very low density lipoproteins that exercise, in spite of promoting healthy aging and health in (VLDLs). Incorporation into the lipoproteins happens via the ␣- general, leads to increased ROS formation tocopherol transfer protein (␣-TTP) which has a higher affinity to In line with the "mitohormesis" concept ( ␣-tocopherol albeit transferring around 10% ␥-tocopherol exercise-induced mitochondrial ROS led to induction of endoge- Therefore ␣-tocopherol supple- nous ROS defense. However, with vitamin E supplementation this mentation is likely to decrease ␥-tocopherol bioavailability and up-regulation of the anti-oxidative resistance was blocked ( the extent up to which the ␣-/␥-tocopherol rates change also Due to its antioxidant properties, vitamin E may abolish depends on the type of vitamin E that is consumed with the this increase in stress resistance (such as the induction of endoge- nous antioxidant enzymes), accounting for the reduced lifespan As a side effect of vitamin E supplementation, increased bleed- observed in many of the studies in model organisms described ing has been reported. Farley et al. gave a possible explanation for this phenomenon by showing that menaquinone (vitamin K) lev- Although in mice the antioxidant properties of vitamin E were els are decreased by high vitamin E tissue concentrations shown to be independent of transcriptional events ( In the context of lifespan extension it is especially vitamin E seems to induce Nrf2 Nrf2 in mammals interesting to note that vitamin K can extend lifespan in C. ele- (or its homologue SKN-1 in C. elegans) is a well known longevity- gans (A putatively negative effect on longevity promoting transcription factor with its target with vitamin E supplementation could therefore be due in part genes encoding for antioxidant proteins and molecules that are to vitamin E ousting the lifespan-prolonging vitamin K from the involved in xenobiotic metabolism (Vitamin E could induce Nrf2 directly through increased Nrf2 expression and Unfortunately, in most studies the vitamin E levels in the model translocation to the nucleus as suggested by (or organisms were not studied and so the amount of the supple- more indirectly by protecting the cell from Nrf2 inhibitors. This mented vitamin E which was bioavailable cannot be given. This mechanism was elucidated in another study with an asthma model is especially relevant in the case of tocopherol acetate supplemen- in which allergens caused inflammation and suppressed Nrf2 in tation because the acetate needs to be hydrolyzed in vivo to exert alveolar macrophages from asthmatics. Administering tocopherol anti-oxidative effects. Therefore, an analysis of vitamin E tissue to these patients could attenuate the allergen-induced Nrf2 inhibi- levels should be conducted in future studies.
tion (It is also possible that vitamin E activates other transcription or longevity factors. The deacetylase sirt1 was 3.3. Adverse effects of vitamin E by induction of drug metabolism shown to have a beneficial effect on aging Sirt1 is a regulator of FoxO transcription factors ␣-Tocopherol with ␥-tocopherol and ␣-tocopherol with vita- are the mammalian homologues of daf-16, a well known longevity min K interactions do not seem to be the only type of interactions gene in C. elegans (While there are still very few for vitamin E. Similar to many prescription drugs, all forms of vita- available data on the effect of vitamin E on sirtuins or FoxOs, a vita- min E are metabolized by Phase I cytochrome P 450 (CYP) enzymes min E analog, ␣-tocopheryl succinate was shown to activate FoxO1 in the liver and seem to be conjugated In the light of a possible effect of vitamin E on by Phase II enzymes before Phase III excretion lifespan and the emerging evidence of its influence on gene expres- In mice, ␣-tocopherol was shown to induce Phase I CYP sion further studies on the interplay of vitamin E and expression (Contrarily, another report states that its cellular targets are needed to understand how this vitamin acts there is no up-regulation of CYP enzymes in vivo and no increased in the organism.
mRNA expression of known CYP drug metabolizers in vitro after administration of ␣-tocopherol In a fur- 3.2. Opposing functions of the tocopherol isoforms and ther study, varying results were found with regard to vitamin E interaction with vitamin K induced CYP up- or down-regulation (How- ever, it seems that Phase II conjugation enzymes A further possible reason for the different outcomes observed and Phase III hepatic transporters ABCB1b and ABCG2 in the studies in this review may be due to the opposing reg- are induced upon vitamin E supplementation. Considering ulatory functions of the different vitamin E isoforms. Indeed, as the finding that vitamin E is eliminated from the organism like described above, Zou et al. reported that whilst low dose ␣- xenobiotics, it seems possible that it decreases the plasma levels tocopherol had a positive effect on the lifespan of flies of the species of co-administered drugs by inducing their enzymatic degradation D. melanogaster, the same dose of ␥-tocopherol had the opposing (This concern is highly relevant considering effect by reducing lifespan In fact, other stud- the fact that in many studies the participating individuals suffer ies have also reported contradictory effects of the two isoforms of from diseases and are accordingly on medication ( tocopherols in vitamin E. Some of these studies showed that toco- pherols can act as pro- or anti-inflammatory agents in endothelial Under such circumstances vitamin E could interfere I.M.A. Ernst et al. / Ageing Research Reviews 12 (2013) 365–375 with the treatment of these diseases and thereby negatively affect Epstein, J., Gershon, D., 1972. Studies on ageing in nematodes IV. The effect of the lifespan of the patients.
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