Vitamin E supplementation and mammalian lifespan

Banks, Ruth; Speakman, John R.; Selman, Colin

doi:10.1002/mnfr.200900382

Cited by 40 publications

(23 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…15 Addition of a-tocopherol partly preserved phosphorylation of Akt and S6, reduced LC3 lipidation upon B10 treatment and significantly reduced B10-induced lysosomal permeabilization and cell death (Supplementary Figure S3). Because a-tocopherol indirectly stimulates PI3K signaling and can exert additional functions, for example, antioxidant functions, 16 we also knocked down TSC2 to activate mTOR. However, silencing of TSC2 had no effect on mTOR signaling in glioblastoma cells and did not rescue the B10-induced LC3 conversion or cytotoxicity (Supplementary Figure S4).…”

Section: Resultsmentioning

confidence: 99%

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

View full text Add to dashboard Cite

In this study, we report a novel mechanism of action for a cytotoxic derivative of betulinic acid (BA). B10 is a semi-synthetic glycosylated derivative of BA selected for its enhanced cytotoxic activity. Interestingly, although B10 induces apoptosis, caspase-3 downregulation incompletely prevents B10-induced cell death, Bcl-2 overexpression fails to protect cells and DNA fragmentation rates do not reflect cell death rates in contrast to cytoplasmic membrane permeabilization. These results implicate that apoptotic and non-apoptotic cell death coexist upon B10 treatment. Unexpectedly, we found that B10 induces autophagy and also abrogates the autophagic flux. B10 destabilizes lysosomes as shown by Lysotracker Red staining and by cathepsin Z and B release from lysosomes into the cytoplasm. Consistently, the cathepsin inhibitor Ca074Me significantly decreases B10-induced cell death, further supporting the fact that the release of lysosomal enzymes contributes to B10-triggered cell death. Downregulation of ATG7, ATG5 or BECN1 by RNAi significantly decreases caspase-3 activation, lysosomal permeabilization and cell death. Thus, by concomitant induction of autophagy and inhibition of the autophagic flux, B10 turns autophagy into a cell death mechanism. These findings have important implications for the therapeutic exploitation of BA derivatives, particularly in apoptosis-resistant cancers. Bioactive natural compounds or their semi-synthetic derivatives offer a considerable therapeutic potential against cancer.1 Among these, betulinic acid (BA), a triterpenoid initially derived from white birch tree, has received attention because of its multiple biological activities in mammalian cells. The pluripotency of BA is of great interest, as this compound is active against HIV, parasitic diseases and cancer.2-5 Nevertheless, the therapeutic application of this drug is currently limited because of its poor solubility in aqueous solvents and an ill-defined mode of action. To overcome these limitations, a wide variety of semi-synthetic derivatives of BA has been generated to improve its pharmacological properties for in vivo studies. In addition, detailed studies are being performed to elucidate the mechanisms of action underlying their cytotoxic activity. To date, BA and its derivatives have been reported to induce cell death in cancer cells via the activation of the intrinsic pathway of apoptosis.6 Accordingly, BA triggers the release of pro-apoptotic factors, such as cytochrome-c, from the mitochondria supposedly by interacting with the permeability pore transition complex and by modifying the balance of pro-and anti-apoptotic proteins of the Bcl-2 protein family. 6 In addition, BA and its derivatives appear to interfere with multiple signaling pathways involved in survival. PI3K, NF-kB and lipid metabolism are modulated by BA-related compounds, but whether and how these effects contribute to cell death is unknown.7-10 A better understanding of the mechanism of action of these compounds is critical to promote their therapeutic...

show abstract

Section: Resultsmentioning

confidence: 99%

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

View full text Add to dashboard Cite

show abstract

“…However, other more biologically relevant dietary antioxidants, which are found in natural food sources, might influence oxidative stress during lactation. For example, vitamin E has, in some studies, been shown to influence mammalian lifespan and levels of oxidative stress, although it is important to note that other studies have failed to find an effect on these parameters (Halliwell and Gutteridge, 1999;Keller et al, 2004;Banks et al, 2010). The diets fed to animals in our study had relatively low levels of vitamin E in relation to levels recommended by the American Society for Nutrition (Reeves et al, 1993) and when compared with levels in a variety of rodent feeds produced across the world (Toime and Brand, 2010), but enough to meet basic nutritional requirements.…”

Section: Discussionmentioning

confidence: 99%

Physiological adaptations to reproduction I. Experimentally increasing litter size enhances aspects of antioxidant defence but does not cause oxidative damage in mice

Garratt

Pichaud

King

et al. 2013

Journal of Experimental Biology

View full text Add to dashboard Cite

SUMMARYLife history theory suggests that investment in reproduction can trade off against growth, longevity and both reproduction and performance later in life. One possible reason for this trade-off is that reproduction directly causes somatic damage. Oxidative stress, an overproduction of reactive oxygen species in relation to cellular defences, can correlate with reproductive investment and has been implicated as a pathway leading to senescence. This has led to the suggestion that this aspect of physiology could be an important mechanism underlying the trade-off between reproduction and lifespan. We manipulated female reproductive investment to test whether oxidative stress increases with reproduction in mice. Each female's pups were cross-fostered to produce litters of either two or eight, representing low and high levels of reproductive investment for wild mice. No differences were observed between reproductive groups at peak lactation for several markers of oxidative stress in the heart and gastrocnemius muscle. Surprisingly, oxidative damage to proteins was lower in the livers of females with a litter size of eight than in females with two pups or non-reproductive control females. While protein oxidation decreased, activity levels of the antioxidant enzyme superoxide dismutase increased in the liver, suggesting this may be one pathway used to protect against oxidative stress. Our results highlight the need for caution when interpreting correlative relationships and suggest that oxidative stress does not increase with enhanced reproductive effort during lactation. Supplementary material available online at

show abstract

“…A lower cancer incidence by the induction of the p21 signaling pathway has been suggested to be the underlying mechanism of the 15% increased lifespan of mice supplemented lifelong with a-TOH (Banks et al 2010). Hypomethylated forms, and particularly the gamma form of TOH, have been observed to activate cell cycle regulators such as p27/Rb both in vitro (Betti et al 2006) and in vivo (Lee et al 2009).…”

Section: Metabolite Formation and Activitymentioning

confidence: 99%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

View full text Add to dashboard Cite

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

show abstract

Vitamin E supplementation and mammalian lifespan

Cited by 40 publications

References 89 publications

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

Physiological adaptations to reproduction I. Experimentally increasing litter size enhances aspects of antioxidant defence but does not cause oxidative damage in mice

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

Contact Info

Product

Resources

About