Age-dependent response of primary human dermal fibroblasts to oxidative stress: cell survival, pro-survival kinases, and entrance into cellular senescence.
A central question in cell biology is how cells become senescent. After a finite number of cell divisions, normal cultured human cells enter a state of irreversible growth arrest, termed "replicative senescence." Alternatively, oxidative stress in the form of hydrogen peroxide (H(2)O(2)) can render human dermal fibroblasts (HDFs) nonproliferative and quiescent, a phenomenon known as stress-induced premature senescence (SIPS). Although critical to the understanding of the pathophysiological basis of many diseases, there is no research to date that has simultaneously examined the interactions between age, oxidative stress, and SIPS. Therefore, the goals of this study were to examine in concert the interactions between these three factors in primary HDFs, and to test our central hypothesis that aging lowers the ability of primary HDFs to respond to oxidative stress. Our data provide, for the first time, evidence that aging dramatically reduces the capacity of primary HDFs to respond to the challenge of hydrogen peroxide. Specifically, aged HDFs showed decreased cell viability, decreased phosphorylation (activation) of pro-survival kinases (Akt and ERK 1/2), and increased entrance into a senescent state when compared with their younger counterparts. Another important conclusion of this study is that blockade of transforming growth factor-beta1 had a pronounced "rescue effect" in the aged, preventing entrance of HDFs into cellular senescence.
Gurjala
Anandev N
AN
Division of Plastic and Reconstructive Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Liu
W Robert
WR
Mogford
Jon E
JE
Procaccini
Piero S A
PS
Mustoe
Thomas A
TA
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001483:Base Sequence; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D018844:Cyclin-Dependent Kinases