A University College London team demonstrates that modulating necroptosis, a regulated necrosis pathway, enhances cellular resilience by pausing harmful death signals and enabling repair. Their preclinical mouse studies reveal improved cognitive function and extended lifespan, indicating therapeutic potential against age-related degeneration.
Key points
Pharmacological inhibition of the RIPK3-MLKL axis to delay regulated necrosis in aged murine models.
Reduced DAMP release lowers neuroinflammation and improves cognitive performance.
Extended median lifespan observed without disrupting essential apoptotic functions.
Why it matters:
Modulating necroptosis shifts anti-aging paradigms by targeting regulated cell death pathways, offering precise intervention over broad-spectrum senolytic approaches.
Q&A
What is necroptosis?
How do necroptosis inhibitors work?
What are DAMPs and why are they important?
Can targeting necroptosis safely improve lifespan?
Read full article
Academy
Necroptosis: A Controlled Form of Cell Death Influencing Aging
Necroptosis is a form of regulated cell death that bridges the gap between apoptosis and uncontrolled necrosis. Unlike apoptosis, which is noninflammatory and involves cell shrinkage and DNA fragmentation, necroptosis leads to plasma membrane rupture and the release of intracellular contents. This process is orchestrated by a distinct signalling cascade involving receptor-interacting protein kinases and mixed lineage kinase domain-like pseudokinase (MLKL).
Key Molecular Players
- RIPK1 and RIPK3: Sensor kinases that form the necrosome complex upon activation by death receptors, such as TNF receptor 1.
- MLKL: Pseudokinase activated by RIPK3 phosphorylation. Oligomerized MLKL translocates to the membrane, causing rupture and DAMP release.
- DAMPs (Damage-Associated Molecular Patterns): Intracellular molecules like HMGB1 and mitochondrial DNA that trigger inflammation when released extracellularly.
Mechanism of Necroptosis Activation
- Initiation: Ligand binding to death receptors (e.g., TNF-α to TNFR1) recruits adaptor proteins and forms complex IIb.
- Necrosome Formation: RIPK1 autophosphorylates and associates with RIPK3 to assemble the necrosome.
- MLKL Activation: RIPK3 phosphorylates MLKL, prompting MLKL oligomerization.
- Execution: MLKL oligomers translocate to the plasma membrane, disrupt lipid bilayers, and induce membrane permeabilization.
- Inflammatory Signalling: Released DAMPs activate pattern recognition receptors (PRRs) on immune cells, driving inflammatory responses.
Role in Aging and Longevity
With age, cells accumulate stress and damage, making them more prone to necroptotic triggers. Chronic, low-grade inflammation driven by DAMPs, known as inflammaging, contributes to tissue degeneration and age-related diseases such as Alzheimer’s and cardiovascular disorders. By modulating necroptosis, researchers aim to reduce DAMP-mediated inflammation, preserve tissue homeostasis, and enhance regenerative capacity.
Therapeutic Approaches
- RIPK1/RIPK3 Inhibitors: Small molecules that block kinase activity to prevent necrosome assembly.
- MLKL Blockers: Peptides or antibodies that interfere with MLKL oligomerization.
- Temporal Control: Short-term dosing regimens to allow repair mechanisms without long-term immune suppression.
Future Directions: Clinical translation requires rigorous safety evaluation. Researchers are exploring targeted delivery systems, such as nanoparticles, to localize inhibitors to aged tissues. Combining necroptosis modulation with senolytics or mitochondrial therapies may yield synergistic effects for comprehensive aging interventions.
Conclusion: Understanding and controlling necroptosis represents a promising frontier in longevity science. By fine-tuning a natural cell death pathway, it is possible to mitigate chronic inflammation, support tissue regeneration, and extend healthspan without compromising essential cellular functions.