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

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

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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