Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging.

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

IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy. · pubmed

Paper

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

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Research summary

Inhibiting the telomeric DNA damage response (tDDR) rescues hematopoietic dysfunction in telomerase-deficient mice, suggesting that targeting the senescence-inducing signaling pathway downstream of telomere shortening can mitigate age-related tissue failure. This work is relevant because it addresses a root cause of aging (telomere attrition) by intervening in the resulting pathological cascade (tDDR) to restore physiological function, rather than merely treating symptoms.

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