A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts


  • K. Jäger
  • J. Mensch
  • M.E. Grimmig
  • B. Neuner
  • K. Gorzelniak
  • S. Türkmen
  • I. Demuth
  • A. Hartmann
  • C. Hartmann
  • F. Wittig
  • A. Sporbert
  • A. Hermann
  • G. Fuellen
  • S. Möller
  • M. Walter


  • Science Advances


  • Sci Adv 8 (33): eabk2814


  • Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.