Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice

Abstract

Male mice receiving vitamin E (5.0 g alpha-tocopherol acetate/kg of food) from 28 wk of age showed a 40% increased median life span, from 61 +/- 4 wk to 85 +/- 4 wk, and 17% increased maximal life span, whereas female mice equally supplemented exhibited only 14% increased median life span. The alpha-tocopherol content of brain and liver was 2.5-times and 7-times increased in male mice, respectively. Vitamin E-supplemented male mice showed a better performance in the tight-rope (neuromuscular function) and the T-maze (exploratory activity) tests with improvements of 9-24% at 52 wk and of 28-45% at 78 wk. The rates of electron transfer in brain mitochondria, determined as state 3 oxygen uptake and as NADH-cytochrome c reductase and cytochrome oxidase activities, were 16-25% and 35-38% diminished at 52-78 wk. These losses of mitochondrial function were ameliorated by vitamin E supplementation by 37-56% and by 60-66% at the two time points considered. The activities of mitochondrial nitric oxide synthase and Mn-SOD decreased 28-67% upon aging and these effects were partially (41-68%) prevented by vitamin E treatment. Liver mitochondrial activities showed similar effects of aging and of vitamin E supplementation, although less marked. Brain mitochondrial enzymatic activities correlated negatively with the mitochondrial content of protein and lipid oxidation products (r2 = 0.58-0.99, P < 0.01), and the rates of respiration and of complex I and IV activities correlated positively (r2 = 0.74-0.80, P < 0.01) with success in the behavioral tests and with maximal life span.

Reverse of Age-Dependent Memory Impairment and Mitochondrial DNA Damage in Microglia by an Overexpression of Human Mitochondrial Transcription Factor A in Mice

“…Many studies have suggested a mechanistic link between mtDNA mutations, a loss of mitochondrial respiratory enzyme functions, and generation of ROS from the mitochondria. A decreased electron transfer activity has been observed in the mitochondria of experimental animals on aging (Navarro et al, 2005;Mao et al, 2006). The activity of complexes I and IV in the mitochondrial fractions prepared from the brain tissue specimens of the aged WT mice were significantly lower compared with the young WT mice, whereas those of complexes II and III were unaffected (Fig.…”

“…Behavioral dysfunctions associated with aging are also postulated to be associated with a decreased activity of mitochondrial electron transfer complexes with aging (Navarro et al, 2004(Navarro et al, , 2005. Furthermore, increased intracellular reactive oxygen species (ROS) activate microglia, which are representative resident mononuclear phagocyte populations in the brain, to induce an increased production of inflammatory mediators (Pawate et al, 2004;Qin et al, 2005).…”

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

“…9 Dietary supplementation with ␣-tocopherol increased significantly the median and maximum (oldest 10%) life span of mice in this study housed at 7 Ϯ 2°C, in accord with previous studies that maintained mice at more benign temperatures. 18,19,21,46 We initiated supplementation at 4 months of age, and the age of initiation and duration of supplementation may be critical in achieving positive life span effects, 19 with studies observing a life span extension generally starting vitamin E/␣-tocopherol supplementation earlier 18,19,46 rather than later in life. 14,24,47 The oxidative stress theory of aging suggests that damage to proteins, lipids, and DNA are a causal factor in the aging process.…”

“…Using a comparative approach, Zou et al 17 reported that ␥-tocopherol, but not ␣-tocopherol, extended life span in Caenorhabditis elegans, but that neither isoform had any life span effect in Drosophila melanogastor or Anastrepha ludens. An increase in median/mean life span has been reported in various strains of mice following vitamin E supplementation [18][19][20][21] or following supplementation with a mixed antioxidant diet containing vitamins E and C. 22 However, other studies report no effect on life span or on oxidative stress following vitamin E supplementation or when using a mixed antioxidant diet. 14,23,24 There are several potential reasons why dietary antioxidants, such as vitamin E, have not become robust and repeatable pro-longevity treatments.…”

Age-Related Mitochondrial Changes after Traumatic Brain Injury

“…There is an ongoing debate concerning the magnitude of decline in mitochondrial respiration that occurs during normal aging (Gilmer et al, 2010). Some groups report extensive age-related declines in mitochondrial respiration (Chiu and Richardson, 1980;Cocco et al, 2005;Navarro et al, 2005Navarro et al, , 2008Petrosillo et al, 2008a,b). Our laboratory and others (Bustamante et al, 2008;Deshmukh et al, 1980;Gilmer et al, 2010;Leslie et al, 1985;Meng et al, 2007) previously reported no significant age-related changes in cortical mitochondrial bioenergetics in naïve rats, while significant elevations in oxidative damage were apparent (Gilmer et al, 2010).…”