Impaired glycolysis in bone underlies age-related bone loss in mice

Abstract

Bone loss and metabolic dysregulation often coexist in older adults, yet the relationship between age-related changes in bone cell metabolism and bone-forming activity remains unclear. By modeling both conditions in aged mice and using in vivo stable-isotope tracing, we demonstrated that age-related decline in bone formation was coupled with an intrinsic impairment of glycolysis within bone tissue. Impaired glycolysis was associated with reduced protein levels of key glycolysis enzymes, and transcriptomics analyses revealed compensatory upregulation of glycolysis genes in aged bone. Metabolic intervention through long-term caloric restriction prevented age-related trabecular bone loss. Furthermore, osteoblast-specific genetic enhancement of glycolysis, via overexpression of HIF1 or the rate-limiting enzyme PFKFB3, significantly improved osteoblast function and increased bone mass in aged mice. Together, the study identifies glycolytic decline as a cell-autonomous driver of osteoblast deficiency and provides proof of principle that reactivating glycolysis can promote bone accrual in aging.

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BibTeX RIS

BibTeX

@misc{song2026impaired,
  title = {{Impaired glycolysis in bone underlies age-related bone loss in mice}},
  author = {F. Song and T. Marmo and W. D. Lee and J. Koehnken Sawall and C. Song and X. Liao and X. Ji and K. Chellappa and M. R. McReynolds and J. A. Baur and C. Thom and F. Long},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.06.738500},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.06.738500v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Impaired glycolysis in bone underlies age-related bone loss in mice
AU  - F. Song
AU  - T. Marmo
AU  - W. D. Lee
AU  - J. Koehnken Sawall
AU  - C. Song
AU  - X. Liao
AU  - X. Ji
AU  - K. Chellappa
AU  - M. R. McReynolds
AU  - J. A. Baur
AU  - C. Thom
AU  - F. Long
PY  - 2026
DA  - 2026/10/06
PB  - bioRxiv
DO  - 10.64898/2026.10.06.738500
UR  - https://www.biorxiv.org/content/10.64898/2026.10.06.738500v1
AB  - Bone loss and metabolic dysregulation often coexist in older adults, yet the relationship between age-related changes in bone cell metabolism and bone-forming activity remains unclear. By modeling both conditions in aged mice and using in vivo stable-isotope tracing, we demonstrated that age-related decline in bone formation was coupled with an intrinsic impairment of glycolysis within bone tissue. Impaired glycolysis was associated with reduced protein levels of key glycolysis enzymes, and transcriptomics analyses revealed compensatory upregulation of glycolysis genes in aged bone. Metabolic intervention through long-term caloric restriction prevented age-related trabecular bone loss. Furthermore, osteoblast-specific genetic enhancement of glycolysis, via overexpression of HIF1 or the rate-limiting enzyme PFKFB3, significantly improved osteoblast function and increased bone mass in aged mice. Together, the study identifies glycolytic decline as a cell-autonomous driver of osteoblast deficiency and provides proof of principle that reactivating glycolysis can promote bone accrual in aging.
ER  -

Abstract

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