Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, the telomere integrity is not only determined by telomere length but also by epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between telomere shortening-induced DDR and epigenetic modification in aging is unknown. Here we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs), and prolongs lifespan of late generation of telomerase deficient mice (G3Terc-/-). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin status for DDR signaling transduction through the demethylating of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a restores the heterochromatin compaction in the sub-telomeric regions and thereby ameliorating the DDR initiation at short telomeres of G3Terc-/- ISCs. Treatment with a small molecule inhibitor of BER alleviates DDR and improves the maintenance and function of G3Terc-/- ISCs. Taken together, our study discloses a potential therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modulating molecules.