SENOMORPHIC EFFECT OF GENETIC AND CHEMICAL PARTIAL REPROGRAMMING

Victor Nuñez-Quintela; Jérémy Chantrel; Miguel Angel Prados; Pablo Pedrosa; Italo Lorandi; Lucia Lorenzo Rodriguez; Cheng Chen; Raquel Paredes-Paredes; Alejandro Failde-Fiestras; Diego Gonzalez‐Perez; Alex Miralles-Dominguez; Sabela Da Silva‐Álvarez; Ramón Lobato-Busto; Miguel González‐Barcia; Clara Alcon; Joan Montero; Patricia Marques; Dafni Chondronasiou; Federico Pietrocola; Manuel Serrano; Marta Kovatcheva; Aurora Gómez-Durán; Han Li; Manuel Collado

doi:10.64898/2026.01.13.699211

Cell BiologybioRxivJan 13, 2026

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SENOMORPHIC EFFECT OF GENETIC AND CHEMICAL PARTIAL REPROGRAMMING

Victor Nuñez-Quintela iD, Jérémy Chantrel iD, Miguel Angel Prados iD, Pablo Pedrosa iD, Italo Lorandi iD, Lucia Lorenzo Rodriguez iD, Cheng Chen iD, Raquel Paredes-Paredes iD, Alejandro Failde-Fiestras iD, Diego Gonzalez‐Perez iD, Alex Miralles-Dominguez iD, Sabela Da Silva‐Álvarez iD, Ramón Lobato-Busto iD, Miguel González‐Barcia iD, Clara Alcon iD, Joan Montero iD, Patricia Marques iD, Dafni Chondronasiou iD, Federico Pietrocola iD, Manuel Serrano iD, Marta Kovatcheva iD, Aurora Gómez-Durán iD, Han Li iD, Manuel Collado iD

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Abstract

Partial reprogramming has emerged as a promising strategy to ameliorate aging phenotypes, yet its cellular targets and mechanisms remain poorly defined. Cellular senescence is a central hallmark of aging and a plausible mediator of reprogramming-induced rejuvenation. Here we show that genetic and chemical partial reprogramming act directly on senescent cells without restoring proliferative capacity. OSKM expression or a reduced two-compound regimen, tranylcypromine and RepSox (2c), attenuates senescence-associated secretory activity, restores mitochondrial homeostasis and apoptotic priming, and improves functional and inflammatory parameters in aged mice, establishing senomorphic, identity-preserving reprogramming as a potentially safer aging intervention.