Transient reprogramming reveals an AP-1–transposable element axis underlying hematopoietic stem cell functional decline during aging and inflammatory stress

Hematopoietic stem cell (HSC) aging involves epigenetic remodeling, but how these changes arise, their relationship to stress-induced alterations, and their reversibility remain unclear. Here, we show that 16-day induction of the Yamanaka factors in young mice delays HSC aging, while in old mice it reverses HSC aging features, improving hematopoietic reconstitution, reducing myeloid bias and DNA damage. Multi-omics revealed that reprogramming induces an early reduction in chromatin accessibility at AP-1-bound regions, preceding aging phenotypes, and attenuates age-associated AP-1 and mesenchymal-drift programs and transposable element (TE) expression. Reverse transcriptase inhibition in aged mice reduced DNA damage and improved HSC function. Reprogramming protected HSCs from chronic LPS-induced premature aging. AP-1 inhibition prevented LPS-induced TE activation, DNA damage and loss of HSC clonogenicity, implicating AP-1-dependent TE activation in HSC decline. Together, these findings show that aged HSCs can be rejuvenated and identify AP-1-associated chromatin remodeling linking inflammatory stress, TE activation, and HSC aging.