AKG-TET axis is central to senescence plasticity

Area of Science:

• Cellular and Molecular Biology
• Aging Research
• Epigenetics

Background:

• Cellular senescence is a stable cell-cycle arrest state associated with aging.
• It is characterized by a pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP).
• The precise molecular mechanisms regulating senescence remain an active area of investigation.

Purpose of the Study:

• To investigate the role of the alpha-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating cellular senescence in human somatic cells.
• To explore how manipulating the AKG-TET axis affects epigenetic reprogramming, inflammatory signaling, and SASP.

Main Methods:

• Genetic downregulation of TET expression using siRNA.
• Pharmacological inhibition of TET activity using C35.
• Limiting AKG bioavailability with a targeting peptide.
• Augmenting AKG bioavailability and TET expression/activity.

Main Results:

• Downregulation of the AKG-TET axis triggered epigenetic reprogramming, amplified pro-inflammatory signaling, and enhanced SASP, driving replicative senescence.
• Augmentation of the AKG-TET axis enhanced cellular resilience to stress.
• Intervention in the AKG-TET axis prevented and reversed senescent phenotypes.

Conclusions:

• The AKG-TET axis is a critical regulator of cellular senescence.
• Cellular senescence is a dynamic and plastic process, not a fixed endpoint.
• The AKG-TET axis represents a potential therapeutic target for interventions related to aging and senescence.