Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging
Year: 2026
Type: article
Abstract: Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. We previously showed that telomere dysfunction induces synthesis of telomeric noncoding RNAs required for activation of the telomeric DNA damage response (tDDR), a driver of senescence and inflammation. However, whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Terc−/− mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors. Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging. Oppezzo and colleagues report that therapeutically blocking telomeric DNA damage signaling reduces senescence and inflammation and restores hematopoietic function in telomerase-deficient and physiologically aged mice.
Source: Nature Aging
Authors: Alessia Oppezzo, Sara Sepe, Giada Cicio, Valeria Cancila, Emanuele Sasso, Anastasia Conti, Eugenia Marinelli, Matteo Cabrini, Rani Pallavi, Nicola Iacomino, Matilde Simoni, Dmitrii Malyshev, Sara Boggio, Alessia di Lillo, Ilaria Rosso, Sara Tavella, Lucrezia A. Trastus, Francesca Rossiello, Giulia Roscia, Paolo Cantaloni, Alessandro Manenti, Paola Cavalcante, Pier Giuseppe Pelicci, Raffaella Di Micco, Alfredo Nicosia, Claudio Tripodo, Fabrizio d’Adda di Fagagna
Institutions: IFOM, University of Palermo, CEINGE Biotecnologie Avanzate Franco Salvatore (Italy), University of Naples Federico II, The San Raffaele Telethon Institute for Gene Therapy, Istituto di Genetica Molecolare, National Research Council, L V Prasad Eye Institute, European Institute of Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Pirogov Russian National Research Medical University, VisMederi (Italy), University of Milan, Istituto Universitario di Studi Superiori di Pavia, Italian Association for Cancer Research
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7166683291