CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres

Lanna, A.; Valvo, S.; Dustin, M.; Rinaldi, F.

doi:10.1101/2025.11.14.688504

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bioRxiv · 10.1101/2025.11.14.688504

CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres

Lanna, A.·Valvo, S.·Dustin, M.·Rinaldi, F.

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Abstract

The role of the immune system in regulating organismal lifespan remains poorly understood. Here, we show that CD4 T cells release "telomere Rivers" into circulation after acquiring telomeres from antigen-presenting cells (APCs). River formation requires fatty acid oxidation at the T cell-APC synapse, which selectively excludes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) from the telomere vesicles. The resulting Rivers are depleted of glycolytic enzymes but enriched in T cell-derived stemness factors, enabling targeted rejuvenation of senescent tissues across multiple organs. In aged mice, adoptive transfer of young or metabolically reprogrammed CD4 T cells triggered River production in vivo, and Rivers isolated from these animals could be transplanted into other aged mice to propagate the rejuvenation phenotype independently of T cells. River therapy extended median lifespan by [~]17 months, with several mice surviving to nearly five years. This immune-driven telomere transfer pathway is conserved across kingdoms, including plants, defining the first systemic, transplantable programme of youth.

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Lanna, A., Valvo, S., Dustin, M., Rinaldi, F.. 2025-11-16. CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres. https://doi.org/10.1101/2025.11.14.688504

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