We found that genes at long distances (up to 10Mb) from telomeres may be regulated differently than the classic telomere position effect (TPE) mechanism. Classic TPE is produced by telomeric heterochromatin invading the subtelomeric region and silencing nearby genes. We discovered that interferon stimulating gene 15 (ISG15, over 1 MB from the telomere) is regulated by telomere length but genes closer to the telomere were not silenced by classic TPE. We called this phenomenon telomere position effect over long distances (or TPE-OLD) to distinguish it from classic TPE. The changes in genomic structure at various loci might provide novel insights into how the regulation of genes in somatic cells is changed during telomere shortening as part of normal aging and how this might lead to a permissive environment for tumor development.