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AbstractAged hematopoietic stem cells (HSCs) show reduced reconstitution potential, limiting their use in transplantation settings in the clinic. We demonstrate here that exposure of aged HSCs ex vivo to a pH of 6.9 instead of the commonly used pH of 7.4 results in enhanced HSCs potential that is consistent with rejuvenation, including attenuation of the myeloid bias of aged HSC and restoration of a youthful frequency of epigenetic polarity. Rejuvenation of aged HSCs by pH 6.9 is, at least in part, due to alterations in the polyamine/methionine pathway within pH 6.9 HSCs, and consequently, attenuation of the production of spermidine also attenuated aging of HSCs. Exposure of aged HSCs to pH 6.9, or pharmacological targeting of the polyamine pathway, might thus extend the use of HSCs from aged donors for therapeutic applications. Aged HSCs show compromised reconstitution potential and myeloid bias. We demonstrate that ex‐vivo exposure of aged HSCs to a pH of 6.9 enhances HSC potential and rejuvenation instead of the commonly used pH 7.4. Moreover, pH 6.9 attenuates the myeloid bias of aged HSC via regulating epigenetic polarity to young levels. These effects correspond to a decrease in the polyamine/methionine pathway of spermidine production and via pharmacological inhibitor, DFMO. This study suggests the prospect of using HSCs from aged donors for HSC transplantation therapy.