A collaboration between the Max Planck Institute for Biology of Ageing and University College London demonstrates that trametinib inhibits RAS/Mek/Erk and rapamycin blocks mTORC1, and together these drugs additively extend healthspan and lifespan in C3B6F1 mice by reducing tumors, inflammation, and age-related metabolic decline.
Key points
Oral trametinib at 1.44 mg/kg diet extends median lifespan by ~10% in male and ~7% in female C3B6F1 mice.
Intermittent rapamycin dosing (42 mg/kg weekly) combined with trametinib yields additive median lifespan gains of 27–35%.
Combination therapy reduces liver and spleen tumor incidence, blocks age-related brain glucose uptake increases, and lowers systemic pro-inflammatory cytokines.
Why it matters:
Dual targeting of RAS/Mek/Erk and mTORC1 pathways offers a promising additive gerotherapeutic strategy with translational potential to enhance mammalian healthspan beyond single-drug approaches.
Q&A
What are geroprotectors?
How does trametinib work against aging?
Why combine trametinib with rapamycin?
What mouse model was used and why?
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Academy
mTORC1 in Longevity Science
mTORC1 (mechanistic Target Of Rapamycin Complex 1) is a critical protein kinase complex that integrates environmental cues to control cell growth, metabolism, and autophagy. It comprises the catalytic subunit mTOR and accessory proteins Raptor, PRAS40, and mLST8. mTORC1 responds to nutrients (amino acids), growth factors (insulin/IGF), energy status (ATP levels), and stress signals to adjust anabolic and catabolic processes.
Key Functions of mTORC1:
- Protein synthesis: mTORC1 phosphorylates S6K1 and 4E-BP1 to increase translation.
- Lipid metabolism: It regulates SREBP transcription factors for fatty acid and cholesterol synthesis.
- Autophagy inhibition: Active mTORC1 phosphorylates ULK1 to suppress the cellular recycling process.
- Ribosome biogenesis: It promotes rRNA transcription for ribosome assembly.
Regulation by Upstream Signals:
- Amino acids: Leucine and arginine activate mTORC1 via the Rag GTPases at the lysosomal surface.
- Growth factors: Insulin/IGF-1 signals through PI3K and AKT, which inhibit the TSC1/2 complex, releasing Rheb GTPase to directly activate mTORC1.
- Energy status: Low ATP/high AMP activates AMPK, which phosphorylates TSC2 and Raptor to inhibit mTORC1 under energy stress.
- Oxygen and stress: Hypoxia and DNA damage activate REDD1 and p53 pathways to suppress mTORC1 activity.
mTORC1 and Aging:
Chronic mTORC1 hyperactivation is linked to accelerated aging, cellular senescence, and age-related diseases including cancer, neurodegeneration, and metabolic disorders. Inhibition of mTORC1 by rapamycin extends lifespan and healthspan in organisms from yeast to mice by:
- Enhancing autophagy and cellular clearance mechanisms.
- Reducing protein synthesis and metabolic overload.
- Lowering inflammation (inflammaging) and tumorigenesis.
- Improving cardiac, immune, and cognitive functions.
Therapeutic Modulation: Rapamycin and its analogs (rapalogs) bind FKBP12 and selectively inhibit mTORC1. While effective, long-term rapamycin can cause side effects like hyperglycemia and immunosuppression. New approaches include:
- Intermittent dosing: Weekly or short-course rapamycin regimens to balance benefits and side effects.
- Combinatorial therapies: Pairing mTORC1 inhibitors with other pathway modulators (e.g., MEK inhibitors like trametinib) to achieve additive geroprotection.
- Targeted delivery: Nanoparticles or prodrugs aimed at specific tissues to reduce systemic toxicity.
Future Directions: Research focuses on identifying optimal dosing schedules, minimizing adverse effects, and combining mTORC1 inhibition with other geroprotectors or lifestyle interventions. Understanding individual variability and biomarker-guided treatments will be key to translating mTORC1‐based therapies into safe human longevity interventions.
