p16INK4A is a robust in vivo biomarker of cellular aging in human skin

Aging Cell. 2006 Oct;5(5):379-89. doi: 10.1111/j.1474-9726.2006.00231.x. Epub 2006 Aug 15.


The cell-cycle regulating gene, p16INK4A, encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an important role in cellular aging and in premature senescence. Although there is an age-dependent increase of p16INK4A expression in human fibroblast senescence in vitro, no data are available regarding the age dependency of p16INK4A in vivo. To determine whether p16INK4A expression in human skin correlates with donor age, p16INK4A expression was analyzed by immunohistochemistry as well as the expression of the p16INK4A repressor BMI1. Samples from the age groups 0-20, 21-70, and 71-95 years were selected from a bank of healthy human skin. We show that the number of p16INK4A positive cells is significantly higher in elderly individuals compared to the younger age groups. The number of p16INK4A positive cells was found to be increased in both epidermis and dermis, compartments with strictly different proliferative activities. BMI1 gene expression was significantly down-regulated with increasing donor age, whereas no striking age differences were observed for Ki67. In immunofluorescence co-expression studies, Ki67-positive cells were negative for p16INK4A and BMI1-expressing cells also stained negatively for Ki67. In conclusion, we provide for the first time evidence that p16INK4A expression directly correlates with chronological aging of human skin in vivo. p16INK4A therefore is a biomarker for human aging in vivo. The data reported here suggest a model for changes in regulatory gene expression that drive aging in human skin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Distribution
  • Biomarkers*
  • Cell Division
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Dermis / metabolism
  • Epidermal Cells
  • Epidermis / metabolism
  • Fluorescent Dyes
  • Gene Expression Regulation / physiology*
  • Humans
  • Immunohistochemistry
  • Indoles
  • Ki-67 Antigen / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Skin / metabolism*


  • BMI1 protein, human
  • Biomarkers
  • Cyclin-Dependent Kinase Inhibitor p16
  • Fluorescent Dyes
  • Indoles
  • Ki-67 Antigen
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • DAPI
  • Polycomb Repressive Complex 1