A joint team from the University of Oklahoma and Kyungpook National University demonstrates that AUF1 binds and destabilizes PGAM1 and PDP2 mRNAs, reducing glycolytic flux and suppressing cellular senescence—offering a novel post-transcriptional angle for anti-aging interventions.
Key points
AUF1 binds and destabilizes PGAM1 and PDP2 mRNAs in human diploid fibroblasts, reducing glycolytic enzyme production.
AUF1 knockout mice exhibit elevated p16/p21 markers and increased IL-6 and TNF-α, confirming accelerated in vivo senescence.
MST1 phosphorylation of AUF1 lifts mRNA suppression under stress, integrating kinase signaling with metabolic reprogramming.
Why it matters:
Linking RNA-binding control of metabolism to senescence unveils a new anti-aging strategy targeting post-transcriptional regulatory axes.
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Academy
AUF1 and Longevity Science
Overview
AUF1 (AU-binding Factor 1) is an essential RNA-binding protein that regulates the stability of numerous messenger RNAs (mRNAs) by recognizing AU-rich elements within their sequences. In the context of longevity science, AUF1 plays a pivotal role in cellular energy balance and aging by fine-tuning the levels of key metabolic enzymes responsible for glycolysis and pyruvate metabolism.
Mechanism of Action
AUF1 binds to specific sequences in the 3’ untranslated regions of target mRNAs encoding glycolytic enzymes such as phosphoglycerate mutase 1 (PGAM1) and pyruvate dehydrogenase phosphatase 2 (PDP2). Upon binding, AUF1 recruits cellular decay machinery to these transcripts, accelerating their degradation and lowering the production of the encoded enzymes. This post-transcriptional regulation reduces glycolytic flux—a hallmark of senescent cells—and helps preserve youthful metabolic profiles.
Link to Cellular Senescence
Cellular senescence is a state of irreversible cell cycle arrest that contributes to age-related tissue dysfunction and chronic inflammation. Senescent cells adopt a high-glycolysis metabolic program to fuel inflammatory secretions and stress responses. By suppressing glycolytic enzymes, AUF1 acts as a brake on this metabolic shift, delaying the onset of senescence and its associated detrimental effects.
Stress Signaling Integration
Mammalian sterile 20-like kinase 1 (MST1) phosphorylates AUF1 under conditions of cellular stress. This modification diminishes AUF1’s affinity for target mRNAs, lifting the repression of glycolytic enzyme expression when cells need to adapt to stress. The MST1-AUF1 axis thus integrates signaling pathways with metabolic control, influencing cell fate decisions between proliferation, senescence and apoptosis.
Therapeutic Implications
Targeting the AUF1 pathway provides a novel strategy for senotherapy—interventions aimed at removing or reprogramming senescent cells to improve tissue health and extend healthspan. Small molecules modulating AUF1 activity or its phosphorylation state, as well as inhibitors of PGAM1 and PDP2, are promising candidates for future anti-aging therapies.
Future Directions
- Investigate tissue-specific roles of AUF1 in diverse aging contexts.
- Develop pharmacological modulators of AUF1-mRNA interactions.
- Explore combination therapies targeting both post-transcriptional regulators and metabolic enzymes.