Jun-Yeong Lee¹, Ian Davis¹, Elliot H. H. Youth^1,2, Jonghwan Kim³, Gary Churchill⁴, Jame Godwin^1,4, Ron Korstanje⁴, Samuel Beck^1,*

¹Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Bar Harbor, ME 04609, USA. ²Brown University, Providence, RI 02912, USA. ³Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. ⁴The Jackson Laboratory, Bar Harbor, ME 04609, USA.

^*Corresponding author. 

Cellular aging is characterized by disruption of the nuclear lamina and its associated heterochromatin. How these structural changes within the nucleus contribute to age-related degeneration of the organism is unclear. Genes lacking CpG islands (CGI− genes) generally associate with heterochromatin when they are inactive. Here, we show that the expression of these genes is globally activated in aged cells and tissues. This CGI− gene misexpression is a common feature of normal and pathological aging in mice and humans. We report evidence that CGI− gene up-regulation is directly responsible for age-related physiological deterioration, notably for increased secretion of inflammatory mediators.