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PKM2 aggregation drives metabolism reprograming during aging process
Juntao Bie1,2, Ridong Li3, Yutong Li1
1Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China.
Nature Communications
|July 9, 2024
Summary
Researchers discovered that pyruvate kinase M2 (PKM2) forms aggregates in aging cells, driving senescence. Small molecules K35 and K27 dissolve these aggregates, alleviating aging and extending lifespan in mice.
Area of Science:
- Biochemistry
- Gerontology
- Molecular Biology
Background:
- Protein aggregation is linked to aging and age-related diseases.
- The specific proteins driving these processes and the potential for therapeutic intervention remain largely unknown.
Purpose of the Study:
- To investigate the role of pyruvate kinase M2 (PKM2) aggregates in cellular senescence and organismal aging.
- To identify compounds that can dissolve PKM2 aggregates and ameliorate aging phenotypes.
Main Methods:
- Formation of PKM2 aggregates in senescent cells and aged mouse tissues was examined.
- A two-step small molecule library screen was conducted to identify aggregate-dissolving compounds.
- The efficacy of identified compounds (K35 and K27) in alleviating senescence and extending lifespan was tested in mouse models.
Main Results:
- PKM2 forms aggregates in senescent cells and aged mouse organs, impairing enzymatic activity and glycolytic flux.
- Compounds K35 and K27 were identified as effective PKM2 aggregate dissolvers.
- Treatment with K35 and K27 reduced aging signatures and extended lifespan in both naturally and prematurely aged mice.
Conclusions:
- PKM2 aggregates play a significant role in inducing cellular senescence and aging phenotypes.
- Targeting PKM2 aggregates presents a potential therapeutic strategy for anti-aging interventions and drug discovery.
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