PotM - July 2026

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

Opezzo, A. et al., Nature Aging 2026

Brief Summary from the authors:

What if some consequences of aging are driven not by the damage itself, but by the alarm signals our cells generate in response to it? More than 20 years ago, we discovered that dysfunctional telomeres activate a DNA damage response (DDR), driving cellular senescence and inflammation. One key question remained: is tissue decline caused by telomere damage itself, or by the persistent signalling it triggers?To answer this, we developed telomeric antisense oligonucleotides (tASO), the first molecules that selectively inhibit telomeric DNA damage signalling.Our new study in Nature Aging shows that tASOs reduce senescence and inflammation, restore hematopoietic stem cell fitness, and improve immune responses to vaccination in mouse models of Telomere Biology Disorders (TBD), physiologically aged mice, and human hematopoietic stem cells from healthy elderly donors—all without elongating telomeres.These findings identify telomeric DNA damage signalling as a causal driver of pathology and support targeting it as a therapeutic strategy. Long-term treatment was well tolerated, with no overt toxicity, no impairment of global DNA damage responses, and no tumor formation.This work offers hope for patients with TBD, bone marrow failure and pulmonary fibrosis, while opening broader opportunities to combat immune aging. It is now moving toward clinical translation through TAG Therapeutics.

Importantly, this scientific journey is now continuing beyond academia, with TAG Therapeutics advancing this approach toward clinical translation.My deepest gratitude goes to Alessia Oppezzo and lab members at IFOM and all collaborators who contributed to this effort, including Claudio Tripodo, Raffaella Di Micco and Alfredo Nicosia and their teams.I am equally grateful to Fondazione Telethon and the European Research Council (ERC), whose long-term support was instrumental in making this work possible.I also acknowledge the broader scientific environment provided by the Consiglio Nazionale delle Ricerche, CNR - DSB Dipartimento Scienze Biomediche, Istituto di Genetica Molecolare "Luigi Luca Cavalli Sforza" - CNR and #PNRR initiatives Age-It and the National Center for Gene Therapy and Drugs based on RNA Technology.

Interview to the corresponding author Dr Fabrizio D'Adda Di Fagagna (IFOM)

What is the potential impact of this work?

Fabrizio commented: “Importantly, this scientific journey is now continuing beyond academia, with TAG Therapeutics advancing this approach toward clinical translation"

What does ICSA represent to you, and how does this paper connect with the ICSA community?

"Scientific discoveries rarely represent an endpoint, More often, they change the questions we ask next. One question now intrigues us: How is cancer controlled by an aged immune system?"