Impaired Polyamine Metabolism Drives Hematopoietic Aging

Hematopoietic ageing is a major driver of morbidity and mortality. A defining hallmark of this process is the skewing of haematopoiesis toward pathological myelopoiesis, a phenomenon tightly linked to metabolic rewiring and epigenetic remodelling of hematopoietic stem and progenitor cells (HSPCs). Polyamines—putrescine, spermidine, and spermine—are essential metabolites involved in key cellular processes such as autophagy, mitochondrial function, and proteostasis. Their biosynthesis declines with age, and spermidine supplementation has been shown to extend lifespan in several model organisms. Yet, how polyamines modulate haematopoiesis remains unknown. Using complementary chemical and genetic approaches, we demonstrate that restricting polyamine biosynthesis specifically in the hematopoietic compartment recapitulates key phenotypic and functional features of hematopoietic ageing. Mechanistically, polyamine deficiency reshapes the transcriptional and epigenetic landscape of HSPCs, enforcing a molecular program that drives aberrant myelopoiesis. Together, our findings uncover a mechanistic link between age-associated metabolic rewiring and epigenetic reprogramming, establishing polyamines as central determinants of stem cell function.