Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway

FEBS Lett. 2006 Oct 16;580(24):5753-8. doi: 10.1016/j.febslet.2006.09.036. Epub 2006 Sep 27.


Klotho has recently emerged as a regulator of aging. To investigate the role of Klotho in the regulation of cellular senescence, we generated stable MRC-5 human primary fibroblast cells knockdown for Klotho expression by RNAi. Downregulation of Klotho dramatically induces premature senescence with a concomitant upregulation of p21. The upregulation of p21 is associated with cell cycle arrest at G1/S boundary. Knockdown of p53 in the Klotho attenuated MRC-5 cells restores normal growth and replicative potential. These results demonstrate that Klotho normally regulates cellular senescence by repressing the p53/p21 pathway. Our findings implicate Klotho as a regulator of aging in primary human fibroblasts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cells, Cultured
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Fibroblasts
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Humans
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • RNA Interference*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation


  • Cyclin-Dependent Kinase Inhibitor p21
  • Insulin
  • Tumor Suppressor Protein p53
  • Insulin-Like Growth Factor I
  • Glucuronidase
  • klotho protein