Intraclonal variation in proliferative potential of human diploid fibroblasts: stochastic mechanism for cellular aging

Science ◽  
1980 ◽  
Vol 207 (4426) ◽  
pp. 82-84 ◽  
Author(s):  
Smith ◽  
R. Whitney
Keyword(s):  
Cellular Aging ◽  
Proliferative Potential ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Stochastic Mechanism

Transcription factor activity during cellular aging of human diploid fibroblasts

1992 ◽  
Vol 70 (10-11) ◽  
pp. 1064-1072 ◽  
Author(s):  
Karl T. Riabowol
Keyword(s):  
Cell Cycle ◽  
Binding Activity ◽  
Cellular Aging ◽  
Proliferative Potential ◽  
Activator Protein 1 ◽  
Direct Role ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Molecular Events

Human diploid fibroblasts display a limited proliferative life span in vitro, which is directly correlated to the age of the donor from which the cells were explanted. In an effort to identify molecular events that may underlie the loss of proliferative potential in aging fibroblasts, we have determined, at the protein level, the abundance of several cell-cycle-regulated proteins and the activity of the two major members of the activator protein-1 (AP-1) DNA binding complex. We find that cyclin A and p34cdc2 expression is decreased by two- to four-fold in old fibroblasts, but that Fos expression and binding activity are reduced by as much as 95% in old, as opposed to young cells, despite equivalent amounts of p105Rb and Jun proteins being expressed. We have further determined that the composition of the protein complex which binds a consensus (-TGACTCA-) AP-1 site changes dramatically during in vitro aging. Since we have shown previously that AP-1 activity is required for progression through the cell cycle, we propose that the quantitative and qualitative changes seen in AP-1 may play a direct role in the gradual loss of proliferative ability seen as cells approach senescence.Key words: cellular aging, Fos, transcription factors.

Cellular aging-dependent decrease in cholesterol in membrane microdomains of human diploid fibroblasts

2003 ◽  
Vol 290 (2) ◽  
pp. 381-390 ◽  
Author(s):  
Megumi Nakamura ◽  
Hiroshi Kondo ◽  
Yukiko Shimada ◽  
Abdul A Waheed ◽  
Yoshiko Ohno-Iwashita
Keyword(s):  
Cellular Aging ◽  
Membrane Microdomains ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts

scholarly journals Gamma-Tocotrienol Modulated Gene Expression in Senescent Human Diploid Fibroblasts as Revealed by Microarray Analysis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Suzana Makpol ◽  
Azalina Zainuddin ◽  
Kien Hui Chua ◽  
Yasmin Anum Mohd Yusof ◽  
Wan Zurinah Wan Ngah
Keyword(s):  
Gene Expression ◽  
Protein Transport ◽  
Expression Patterns ◽  
Gene List ◽  
Enrichment Analysis ◽  
Cellular Aging ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts

The effect ofγ-tocotrienol, a vitamin E isomer, in modulating gene expression in cellular aging of human diploid fibroblasts was studied. Senescent cells at passage 30 were incubated with 70 μM ofγ-tocotrienol for 24 h. Gene expression patterns were evaluated using Sentrix HumanRef-8 Expression BeadChip from Illumina, analysed using GeneSpring GX10 software, and validated using quantitative RT-PCR. A total of 100 genes were differentially expressed (P<0.001) by at least 1.5 fold in response toγ-tocotrienol treatment. Amongst the genes wereIRAK3, SelS, HSPA5, HERPUD1, DNAJB9, SEPR1, C18orf55, ARF4, RINT1, NXT1, CADPS2, COG6, andGLRX5. Significant gene list was further analysed by Gene Set Enrichment Analysis (GSEA), and the Normalized Enrichment Score (NES) showed that biological processes such as inflammation, protein transport, apoptosis, and cell redox homeostasis were modulated in senescent fibroblasts treated withγ-tocotrienol. These findings revealed thatγ-tocotrienol may prevent cellular aging of human diploid fibroblasts by modulating gene expression.

scholarly journals Inhibition of Mitochondrial CytochromecRelease and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Suzana Makpol ◽  
Norhazira Abdul Rahim ◽  
Chua Kien Hui ◽  
Wan Zurinah Wan Ngah
Keyword(s):  
Caspase 3 ◽  
Annexin V ◽  
Telomerase Activity ◽  
Cellular Aging ◽  
Premature Senescence ◽  
Caspase 9 ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Apoptotic Effect ◽  
Stress Induced Premature Senescence

In this study, we determined the molecular mechanism ofγ-tocotrienol (GTT) in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs). Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associatedβ-galactosidase (SAβ-gal) and promoted G0/G1cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochromecrelease and increased activation of caspase-9 and caspase-3 (P<0.05). GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochromecrelease and decreased activation of caspase-9 and caspase-3 (P<0.05). Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P<0.05) in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochromecrelease from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

scholarly journals Expression of Senescence-Associated microRNAs and Target Genes in Cellular Aging and Modulation by Tocotrienol-Rich Fraction

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Sharon Gwee Sian Khee ◽  
Yasmin Anum Mohd Yusof ◽  
Suzana Makpol
Keyword(s):  
Cellular Senescence ◽  
Target Genes ◽  
Replicative Senescence ◽  
Primary Cultures ◽  
Ectopic Expression ◽  
Cellular Aging ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Tocotrienol Rich Fraction

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.

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