Inosine promotes erythrocyte metabolic reprogramming and restores oxygen release for rejuvenation via 2,3-BPG-PNP axis

  • Cell Discov. 2026 Mar 17;12(1):19. doi: 10.1038/s41421-026-00877-6.
Wuping Liu  #  1  2 ,  Zhaoyu Yang  #  1  3 ,  Changhan Chen  #  1  2 ,  Fang Yu  #  1  4 ,  Mengzhi Wu  1  2 ,  Zhouzhou Yao  1  2 ,  Yuhua Fan  1  5 ,  Tingting Xie  1  6 ,  Linlin Wan  1  7 ,  Tiansheng Chou  1  2 ,  Xianjing Feng  1  4 ,  Hao Qi  1  2 ,  Yuyu Chou  1  2 ,  Juan Zhao  2  8 ,  Juan Liu  1  2 ,  Zhiyu Yang  1  2 ,  Yujin Zhang  1  2 ,  Rodney E Kellems  1  9 ,  Yang Xia  10  11  12  13
Affiliations
  • 1. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 3. Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6. Department of General Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 7. Department of Radiology; Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 8. Department of Laboratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 9. Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA.
  • 10. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 11. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 12. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 13. Furong Laboratory, Changsha, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 41844569 DOI: 10.1038/s41421-026-00877-6
Abstract

Aging-related diseases are aggravated by tissue hypoxia; however, the underlying mechanism remains unknown. Here, we report that the oxygen (O2) release capacity of red blood cells (RBCs) gradually decreases with age and is closely associated with aging-related tissue dysfunction. Metabolomic profiling of human and mouse RBCs and genetic studies in mice revealed that the reduction in 2,3-bisphosphoglyceric acid (2,3-BPG) content mediated by a decrease in bisphosphoglycerate mutase (BPGM) activity is a metabolic checkpoint underlying decreased RBC O2 release capability and dysfunction with advancing age. When glucose metabolism is impaired, erythroid inosine, transported by equilibrative nucleoside transporter 1 and converted to ribose 1-phosphate by increased purine nucleoside Phosphorylase (PNP) activity, is an important compensatory fuel for RBCs during aging. In a preclinical study, inosine supplementation successfully alleviated the age-dependent reduction in BPGM activity that mediates glucose metabolic impairment, decreased O2 delivery, and tissue dysfunction. Finally, we unexpectedly discovered that 2,3-BPG acts as an inhibitor of PNP in RBCs by competing with the phosphate (Pi)-binding domain and interacting with residues serine 33 and alanine 116. Our studies revealed that impaired glucose metabolic reprogramming resulting from decreased BPGM activity underlies RBC bioenergetic decline and is a novel hallmark of aging. As 2,3-BPG levels decrease during aging, its inhibitory effect on PNP is reduced, resulting in increased PNP activity and inosine catabolism as an alternative fuel, suggesting that inosine is a potential rejuvenating therapy.

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