Telomeric DDR blockade rejuvenates aging hematopoiesis
Therapeutic inhibition of telomeric DNA damage response using telomeric antisense oligonucleotides (tASO) suppresses tDDR signaling in telomerase-deficient mice and physiologically aged mice, reducing cellular senescence and inflammation, restoring hematopoietic tissue architecture, enhancing hematopoietic stem/progenitor cell quiescence and fitness, and improving in vivo repopulation and humoral immune responses; ex vivo human aged CD34+ HSPCs also show improved clonogenic potential. Telomere length is unchanged, indicating relief of dysfunction via tDDR blockade rather than telomere elongation, suggesting tDDR inhibition as a therapeutic strategy for telomere biology disorders and age-related hematopoietic aging.