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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:4-9 (2005)
© 2005 The Gerontological Society of America

Down-Regulation of a Forkhead Transcription Factor, FOXO3a, Accelerates Cellular Senescence in Human Dermal Fibroblasts

Hyun Kyoung Kim1, Yu Kyoung Kim1, In-Hwan Song2, Suk-Hwan Baek1, Seung-Rock Lee3, Jung Hye Kim1 and Jae-Ryong Kim1,

1 Department of Biochemistry and Molecular Biology
2 Department of Anatomy, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
3 Department of Biochemistry, Chonbuk National University Medical School, Chonju, Republic of Korea.

Address correspondence to Jae-Ryong Kim, Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong, Daegu 705-717, Republic of Korea. E-mail:kimjr{at}med.yu.ac.kr

The signaling pathway of insulin/insulin-like growth factor/phosphatidylinositol-3 kinase/Akt/forkhead transcription factors is known to control life span and senescence in organisms ranging from yeast to mice. The FOXO family of forkhead transcription factors, FOXO1, FOXO3a, and FOXO4, play a critical role in this signal transduction pathway. However, the impact of FOXO3a activation on life span of primary cultured human dermal fibroblasts (HDFs) is unknown. To investigate the role of FOXO3a in the regulation of cellular senescence, we prepared FOXO3a-siRNA stable HDFs. We found that the down-regulation of FOXO3a RNA and protein in HDFs induced many senescent phenotypes, including changes in cell morphology, increases in population doubling times, senescence-associated ß-galactosidase staining and the cellular reactive oxygen species, and up-regulation of p53/p21 protein expression. Our data provide evidence of the key role of FOXO3a transcription factor as a mediator of cellular senescence in HDFs, and suggest that the mechanism of senescence is conserved in HDFs.




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R. ARKING
Multiple Longevity Phenotypes and the Transition from Health to Senescence
Ann. N.Y. Acad. Sci., December 1, 2005; 1057(1): 16 - 27.
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