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Vitamin E Supplementation Delays Cellular Senescence In Vitro.

ABSTRACT: Vitamin E is an important antioxidant that protects cells from oxidative stress-induced damage, which is an important contributor to the progression of ageing. Ageing can be studied in vitro using primary cells reaching a state of irreversible growth arrest called senescence after a limited number of cellular divisions. Generally, the most utilized biomarker of senescence is represented by the expression of the senescence associated ?-galactosidase (SA-?-gal). We aimed here to study the possible effects of vitamin E supplementation in two different human primary cell types (HUVECs and fibroblasts) during the progression of cellular senescence. Utilizing an unbiased automated system, based on the detection of the SA-?-gal, we quantified cellular senescence in vitro and showed that vitamin E supplementation reduced the numbers of senescent cells during progression of ageing. Acute vitamin E supplementation did not affect cellular proliferation, whereas it was decreased after chronic treatment. Mechanistically, we show that vitamin E supplementation acts through downregulation of the expression of the cycline dependent kinase inhibitor P21. The data obtained from this study support the antiageing properties of vitamin E and identify possible mechanisms of action that warrant further investigation.

SUBMITTER: La Fata G

PROVIDER: S-EPMC4647025 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Vitamin E Supplementation Delays Cellular Senescence In Vitro.

La Fata Giorgio G Seifert Nicole N Weber Peter P Mohajeri M Hasan MH

BioMed research international 20151103

Vitamin E is an important antioxidant that protects cells from oxidative stress-induced damage, which is an important contributor to the progression of ageing. Ageing can be studied in vitro using primary cells reaching a state of irreversible growth arrest called senescence after a limited number of cellular divisions. Generally, the most utilized biomarker of senescence is represented by the expression of the senescence associated β-galactosidase (SA-β-gal). We aimed here to study the possible ...[more]

PMID: 26613084

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Project description:Increased cell senescence contributes to the pathogenesis of aging and aging-related disease. Senescence of human fibroblasts in vitro may be delayed by culture in low glucose concentration. There is also accumulating evidence of senescence delay by exposure to dietary bioactive compounds that activate transcription factor Nrf2. The mechanism of cell senescence delay and connection between these responses is unknown. We describe herein that the cruciferous vegetable-derived metabolite, sulforaphane (SFN), activates Nrf2 and delays senescence of human MRC-5 and BJ fibroblasts in vitro. Cell senescence is associated with a progressive and marked increased rate of glucose metabolism through glycolysis. This increases mitochondrial dysfunction and overwhelms defences against reactive metabolites, leading to increasing proteomic and genomic oxidative damage. Increased glucose entry into glycolysis in fibroblast senescence is mainly mediated by increased hexokinase-2. SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic-like activity and thereby decreased oxidative damage to cell protein and DNA. This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells; decreased hexokinase-2, curbing entry of glucose into cellular metabolism; decreased 6-phosphofructo-2-kinase, downregulating formation of allosteric enhancer of glycolysis fructose-2,6-bisphosphate; and increased glucose-6-phosphate dehydrogenase, downregulating carbohydrate response element- (ChRE-) mediated transcriptional enhancement of glycolysis by Mondo/Mlx. SFN also enhanced clearance of proteins cross-linked by transglutaminase which otherwise increased in senescence. This suggests that screening of compounds to counter senescence-associated glycolytic overload may be an effective strategy to identify compounds with antisenescence activity and health beneficial effects of SFN in longevity may involve delay of senescence through glucose and glycolytic restriction response.

Project description:Calorie restriction (CR) is a nongenetic intervention with a robust effect on delaying aging in mammals and other organisms. A mild stimulation on mitochondrial biogenesis induced by CR seems to be an important action mode for its benefits. Here, we reported that a component isolated from Rhodiola rosea L., salidroside, delays replicative senescence in human fibroblasts, which is related to its stimulation on mitochondrial biogenesis by activating SIRT1 partly resulted from inhibition on miR-22. Salidroside increased the mitochondrial mass that accompanied an increment of the key regulators of mitochondrial biogenesis including PGC-1α, NRF-1, and TFAM and reversed the mitochondrial dysfunction in presenescent 50PD cells, showing a comparable effect to that of resveratrol. SIRT1 is involved in the inducement of mitochondrial biogenesis by salidroside. The declined expression of SIRT1 in 50PD cells compared with the young 30PD cells was prevented upon salidroside treatment. In addition, pretreatment of EX-527, a selective SIRT1 inhibitor, could block the increased mitochondrial mass and decreased ROS production induced by salidroside in 50PD cells, resulting in an accelerated cellular senescence. We further found that salidroside reversed the elevated miR-22 expression in presenescent cells according to a miRNA array analysis and a subsequent qPCR validation. Enforced miR-22 expression by using a Pre-miR-22 lentiviral construct induced the young fibroblasts (30PD) into a senescence state, accompanied with increased senescence-related molecules including p53, p21, p16, and decreased SIRT1 expression, a known target of miR-22. However, salidroside could partly impede the senescence progression induced by lenti-Pre-miR-22. Taken together, our data suggest that salidroside delays replicative senescence by stimulating mitochondrial biogenesis partly through a miR22/SIRT1 pathway, which enriches our current knowledge of a salidroside-mediated postpone senility effect and provides a new perspective on the antidecrepitude function of this naturally occurring compound in animals and humans.

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Vitamin E Supplementation Delays Cellular Senescence In Vitro.

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Vitamin E Supplementation Delays Cellular Senescence In Vitro.

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