Summary Interstitial Telomere Sequences (ITS tracts) are degenerate telomere repeat tracts found on metazoan chromosome arms whose functional significance is not known. We propose to develop a new paradigm in the field of telomere biology, by demonstrating a telomere binding protein in somatic cells regulates a suite of stress response and longevity genes that possess introns with ITS tracts. We discovered that ITS tracts are enriched in the introns of C. elegans genes, and this is also true in humans. We identified hundreds of C. elegans genes with ITS tracts that are bound by a telomere binding protein. The vast majority of these genes are upregulated in response to environmental stresses and in mutants that are long-lived and stress resistant. We discovered environmental stresses that alter localization of telomere binding proteins to telomeres of embryos and as well as nuclear localization in somatic cells of L4 larvae. We propose to characterize how environmental stresses and longevity pathways epigenetically reprogram the expression of genes whose introns possess ITS tracts, in part by remodeling the structures of ITS tracts of genes with roles in stress resistance and longevity. Preliminary data indicate that mutating the single-stranded telomere binding protein pot-1 impedes binding of all single-stranded telomere binding proteins to telomeres. Moreover, pot-1 mutation also induces moderate longevity, and both longevity and disrupted telomere capping phenotypes can be transmitted by pot- 1 mutant gametes to multiple generations of progeny that possess wild type POT-1 protein. We propose to study the heritable consequences of telomere uncapping in pot-1 mutant germ cells on expression of genes with ITS tracts. We will ask if longevity of long-lived mutants, including pot-1 mutants, grown with or without arsenic is modified by RNAi silencing of ITS tracts or by re-wiring the expression of dsDNA telomere binding proteins. We will assess the consequences of te