A team at Fudan University demonstrates that phosphorylation at threonine 603 of the Mediator subunit MED15 by CDK1 under TGFβ signaling drives the senescence-associated secretory phenotype (SASP). Mutating T603 to alanine enhances FOXA1 binding to suppress SASP gene expression, alleviating tissue inflammation and cognitive decline in aging mice, suggesting a novel target for age-related pathologies.
Key points
CDK1 phosphorylates MED15 at T603 under TGFβ stimulation to promote SASP gene expression and cellular senescence.
MED15 T603A dephosphorylation mutant enhances FOXA1 binding at SASP gene promoters, reducing Pol II recruitment and inflammatory cytokine production.
Med15 T604A knock-in mice display reduced systemic SASP factor levels, preserved hippocampal synaptic function, and improved memory and learning.
Why it matters:
Modulating MED15 T603 phosphorylation could transform aging research by selectively suppressing SASP-driven inflammation and preserving cognitive function in age-related diseases.
Q&A
What is the senescence-associated secretory phenotype (SASP)?
How does MED15 phosphorylation at T603 regulate gene expression?
What role does FOXA1 play in suppressing SASP genes?
How does dephosphorylation of MED15 improve cognitive function in mice?
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Academy
Senescence-Associated Secretory Phenotype (SASP)
Senescence-Associated Secretory Phenotype (SASP) refers to the ensemble of factors secreted by cells that have entered a state of permanent growth arrest called senescence. Rather than simply halting cell division, senescent cells adopt a specialized secretory program, releasing signaling proteins such as cytokines, chemokines, growth factors and proteases. These secreted molecules communicate stress or damage to neighboring cells and the immune system. While SASP can promote tissue repair and remodeling by recruiting immune cells to clear damaged cells, chronic SASP drives inflammation, tissue dysfunction and progression of age-related diseases like fibrosis, neurodegeneration and cancer.
Mechanisms of SASP Activation
Cells become senescent in response to a variety of stressors—telomere shortening after many divisions, DNA damage from radiation or chemicals, oncogene activation, oxidative stress or mitochondrial dysfunction. These triggers converge on signaling pathways including p53/p21 and p16/retinoblastoma (RB), enforcing stable cell cycle arrest. Simultaneously, the inflammatory arm of SASP is activated through transcription factors such as NF-κB and C/EBPβ. Upstream signals like TGFβ (transforming growth factor beta) engage kinases such as CDK1 to phosphorylate key transcriptional cofactors (for example, MED15) and relieve repression of SASP genes, enabling full SASP expression.
Impact on Aging and Disease
During healthy aging, senescent cells are typically cleared by immune surveillance. However, with age the efficiency of this clearance declines, allowing senescent cells to accumulate. Continuous SASP secretion fosters a pro-inflammatory environment, disrupting normal tissue architecture and function. In the brain, persistent SASP contributes to chronic neuroinflammation, impairing synaptic transmission and accelerating cognitive decline. In other organs like the liver, lung and muscle, SASP drives fibrosis and degenerative changes, linking cellular senescence tightly to organismal aging.
Therapeutic Approaches Targeting SASP
- Senolytics: Small molecules that selectively induce apoptosis of senescent cells, reducing SASP burden.
- Senomorphics: Compounds that suppress SASP expression without killing senescent cells, often by inhibiting SASP regulators such as NF-κB, p38MAPK or CDK1.
- Immune Modulation: Boosting immune clearance of senescent cells via cytokine therapies or checkpoint inhibitors.
- Epigenetic Modifiers: Targeting chromatin remodelers like Mediator subunits (e.g., MED15) to reinforce repression of SASP gene clusters.
Future Directions in Longevity Science
Understanding the precise molecular switches that control SASP—such as phosphorylation of Mediator components—offers targeted strategies to modulate senescence without disrupting essential growth arrest. By fine-tuning SASP activity, researchers aim to restore tissue homeostasis, reduce chronic inflammation and preserve organ function. These interventions hold promise for delaying aging phenotypes and treating age-related diseases, ushering in a new era of precision geroscience.
