PKM2 aggregation drives metabolism reprograming during aging process

Juntao Bie, Ridong Li, Yutong Li, Chen Song, Zhaoming Chen, Tianzhuo Zhang, Zhiheng Tang, Li Su, Liangyi Zhu, Jiaxin Wang, You Wan, Jun Chen (), Xiaoyun Liu (), Tingting Li () and Jianyuan Luo ()
Additional contact information
Juntao Bie: Peking University Health Science Center
Ridong Li: Peking University Health Science Center
Yutong Li: Peking University Health Science Center
Chen Song: Peking University Health Science Center
Zhaoming Chen: Peking University Health Science Center
Tianzhuo Zhang: Peking University Cancer Hospital & Institute
Zhiheng Tang: Peking University Health Science Center
Li Su: Peking university medical and health analysis center
Liangyi Zhu: Peking University Health Science Center
Jiaxin Wang: Peking University
You Wan: Peking University
Jun Chen: Peking University
Xiaoyun Liu: Peking University Health Science Center
Tingting Li: Peking University Health Science Center
Jianyuan Luo: Peking University Health Science Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract While protein aggregation’s association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

Date: 2024
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DOI: 10.1038/s41467-024-50242-y

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