Hematopoietic telomerase delays premature aging through a telomere-independent immune–microbiota axis

Aging is driven by the interplay between immune dysfunction, microbiome dysbiosis and telomere attrition, yet how these hallmarks interact in vivo, and whether they can be therapeutically uncoupled, remains poorly understood. Here we use Rag1-deficient zebrafish, a vertebrate model of adaptive immune deficiency and premature inflammaging, to show that the gut microbiota and hematopoietic telomerase act as key, targetable modulators of immune-driven aging. Loss of adaptive immunity triggers premature intestinal degeneration, barrier dysfunction, systemic inflammation and progressive dysbiosis dominated by Pseudomonadota expansion. Depleting the microbiota rescues survival and attenuates intestinal and systemic inflammatory signatures, while transfer of rag1 ^−/− microbiota into immunocompetent hosts is sufficient to transmit mutant-like molecular features, establishing dysbiosis as a causal amplifier of the phenotype. Telomerase activity also shapes disease progression: genetic telomerase loss accelerates mortality, whereas tert overexpression specifically in hematopoietic cells extends lifespan, reprograms the hematopoietic transcriptome, and partially restores gut, liver and microbiota homeostasis. Notably, this rescue occurs without major changes in telomere length, indicating that hematopoietic telomerase acts through telomere-independent reprogramming of immune cell states rather than telomere elongation per se. Together, these findings define a functional immune-microbiota–telomerase axis controling premature aging and identify hematopoietic telomerase as a non-canonical regulator of immune and organismal homeostasis, with potential relevance for human immunosenescence and inflammaging.