Abstract
Emerging evidences highlight the implication of microRNAs as a posttranscriptional regulator in aging. Several senescence-associated microRNAs (SA-miRNAs) are found to be differentially expressed during cellular senescence. However, the role of dietary compounds on SA-miRNAs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on SA-miRNAs (miR-20a, miR-24, miR-34a, miR-106a, and miR-449a) and established target genes of miR-34a (CCND1, CDK4, and SIRT1) during replicative senescence of human diploid fibroblasts (HDFs). Primary cultures of HDFs at young and senescent were incubated with TRF at 0.5 mg/mL. Taqman microRNA assay showed significant upregulation of miR-24 and miR-34a and downregulation of miR-20a and miR-449a in senescent HDFs (P < 0.05). TRF reduced miR-34a expression in senescent HDFs and increased miR-20a expression in young HDFs and increased miR-449a expression in both young and senescent HDFs. Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P < 0.05). TRF inhibited miR-34a expression thus relieved its inhibition on CDK4 gene expression. No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53. In conclusion tocotrienol-rich fraction prevented cellular senescence of human diploid fibroblasts via modulation of SA-miRNAs and target genes expression.
Highlights
Tocotrienols, the lesser known isomer of vitamin E, have gained increasing scientific interest in the study of aging and aging-related diseases due to its eminent antioxidant effects and nonantioxidant activity [1]
Positive blue stain of SA-β-gal staining mainly appeared in human diploid fibroblasts (HDFs) at passage 30 suggesting that HDFs at this passage had reached senescence (Figures 1(c) and 1(d))
Young HDFs were transfected with miR-34a mimic (10 nM) to overexpress miR-34a or miRNA negative control as control for 24 h, followed by tocotrienol-rich fraction (TRF) treatment for 24 h. adenotes P < 0.05 compared to control young untransfected HDFs, bP < 0.05 compared to young HDFs transfected with miRNA negative control, and cP < 0.05 compared to control senescent HDFs
Summary
Tocotrienols, the lesser known isomer of vitamin E, have gained increasing scientific interest in the study of aging and aging-related diseases due to its eminent antioxidant effects and nonantioxidant activity [1]. Palm oil is one of the richest natural sources of tocotrienol. Tocotrienol extracted from palm oil consists mainly of α-tocopherol and a mixture of four tocotrienol isomers (α, β, γ, and δ), referred to as tocotrienol-rich fraction (TRF) [2]. Accumulating evidences demonstrated that tocotrienol modulates several mechanisms associated with aging. In individuals over 50 years old, tocotrienol-rich fraction supplementation decreased DNA damage [3] and reduced the level of advanced glycosylation end products (AGE) and protein carbonyls, which are the oxidative damage indicators during aging [4]. In animal model of aging, tocotrienol extended mean lifespan by reducing protein carbonylation [5]. In replicative cell aging model, tocotrienol-rich fraction reversed cellular aging by preventing cell cycle arrest while restoring telomere length [6]
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