Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations

Yuan Wang, Peng Deng, Yuting Liu, Yunshu Wu, Yaqian Chen, Yuchen Guo, Shiwen Zhang, Xiaofei Zheng, Liyan Zhou, Weiqing Liu, Qiwen Li, Weimin Lin, Xingying Qi, Guomin Ou, Cunyu Wang and Quan Yuan ()
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Yuan Wang: Sichuan University
Peng Deng: UCLA
Yuting Liu: Sichuan University
Yunshu Wu: Sichuan University
Yaqian Chen: Sichuan University
Yuchen Guo: Sichuan University
Shiwen Zhang: Sichuan University
Xiaofei Zheng: Sichuan University
Liyan Zhou: Sichuan University
Weiqing Liu: Sichuan University
Qiwen Li: Sichuan University
Weimin Lin: Sichuan University
Xingying Qi: Sichuan University
Guomin Ou: Sichuan University
Cunyu Wang: UCLA
Quan Yuan: Sichuan University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.

Date: 2020
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DOI: 10.1038/s41467-020-19360-1

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