Hypothesis: Targeting p90RSK to Unlock Longevity – A Druggable Path Beyond IL-11

Aging is a complex biological process characterized by a progressive decline in physiological function and an increased risk of age-related diseases. Geroscience aims to intervene in these fundamental aging mechanisms to extend healthy lifespan. Recent breakthroughs have illuminated novel pathways, and among them, the interleukin-11 (IL-11) signaling axis has emerged as a compelling target.

The IL-11 Link to Aging: A Master Regulator Unveiled

A landmark study published in Nature in 2024 by Widjaja et al. demonstrated that IL-11, a pro-inflammatory cytokine, is progressively upregulated across various cell types and tissues with age [1]. Crucially, genetic deletion of Il11 or its receptor Il11ra1, or pharmacological inhibition of IL-11 in aged mice, significantly extended median lifespan by 22.5% to 25% and improved multiple healthspan parameters, including metabolism and muscle function [1].

This research revealed that IL-11 exerts its pro-aging effects by regulating a critical intracellular signaling cascade: the ERK–AMPK–mTORC1 axis. Specifically, IL-11 stimulates the ERK/p90RSK pathway [2].

p90RSK: The Underappreciated Node in the Longevity Network

While IL-11 itself is a promising target, its downstream effector, p90 ribosomal S6 kinase (p90RSK), presents an equally, if not more, attractive druggable target. The Widjaja et al. study elucidated that IL-11-stimulated ERK/p90RSK activity directly causes the phosphorylation of Liver Kinase B1 (LKB1) at serine residues S325 and S428 [2] [3] [4]. This phosphorylation event leads to the inactivation of LKB1, which is a master upstream kinase of AMP-activated protein kinase (AMPK). Consequently, LKB1 inactivation results in the inhibition of AMPK and the activation of mechanistic Target of Rapamycin Complex 1 (mTORC1) [2] [3] [4].

The LKB1/AMPK pathway is a well-established guardian of cellular energy homeostasis and a key longevity pathway, while mTORC1 is a central regulator of cell growth, proliferation, and aging. Thus, IL-11, through p90RSK, actively sabotages a fundamental pro-longevity pathway.

A Druggable Opportunity: Repurposing p90RSK Inhibitors

The beauty of targeting p90RSK lies in its established druggability. Several p90RSK inhibitors are already in various stages of clinical development for other indications, primarily cancer:

PMD-026, a first-in-class oral pan-RSK inhibitor, is currently in Phase 2 clinical trials (NCT04115306) for metastatic breast cancer [5]. Its safety and pharmacokinetic profile are being characterized in humans, providing a significant head start for potential repurposing in aging. Similarly, BI-D1870 has been extensively used in preclinical research as a p90RSK inhibitor [6].

The Hypothesis: Inhibiting p90RSK for Longevity

We hypothesize that pharmacological inhibition of p90RSK could serve as a novel, druggable strategy to extend healthspan and lifespan by reversing the age-associated inactivation of LKB1/AMPK and subsequent activation of mTORC1. By blocking p90RSK, we aim to:

1. Reactivate LKB1: Prevent the phosphorylation of LKB1 at S325 and S428, thereby restoring its activity.
2. Boost AMPK Activity: Allow LKB1 to activate AMPK, promoting cellular energy sensing, catabolism, and stress resistance.
3. Inhibit mTORC1: Downregulate mTORC1 signaling, mimicking the effects of caloric restriction and rapamycin, which are known to extend lifespan.

This approach offers a more direct intervention in the core longevity pathway modulated by IL-11, potentially bypassing other pleiotropic effects of direct IL-11 inhibition. Given the existing clinical data for PMD-026, this hypothesis presents a high-confidence, translational opportunity for drug repurposing in geroscience.

Key Risks and Future Directions

While promising, potential risks include off-target effects of p90RSK inhibitors, given the enzyme's role in various cellular processes. However, the existing clinical data for PMD-026 in cancer patients will provide valuable insights into its safety profile. Future research should focus on:

• Preclinical validation: Rigorous testing of PMD-026 or other selective p90RSK inhibitors in diverse aging models to confirm healthspan and lifespan benefits.
• Biomarker identification: Developing biomarkers to monitor p90RSK inhibition and its downstream effects on LKB1/AMPK/mTORC1 in aging tissues.
• Clinical trials: Initiating early-phase clinical trials to assess the safety and efficacy of p90RSK inhibitors in older adults, potentially starting with individuals at high risk for age-related metabolic decline or frailty.

By targeting p90RSK, we may unlock a powerful new avenue for therapeutic intervention in aging, leveraging existing pharmaceutical assets to accelerate the development of longevity medicines.

References

[1] Widjaja, A. A., Lim, W. W., Viswanathan, S., Chothani, S., Ting, J. G. W., Tan, J., ... & Cook, S. A. (2024). Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature, 632(8023), 157-165. PMID: 39020175 [2] Widjaja, A. A., Viswanathan, S., Ting, J. G. W., Tan, J., Shekeran, S. G., Carling, D., ... & Cook, S. A. (2022). IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells. iScience, 25(9), 104806. PMID: 35992082 [3] Widjaja, A. A., Viswanathan, S., Ting, J. G. W., Tan, J., Shekeran, S. G., Carling, D., ... & Cook, S. A. (2022). IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR in hepatocytes, the stroma and cancer cells. bioRxiv, 2022-02. DOI: 10.1101/2022.02.10.479876 [4] Widjaja, A. A., Viswanathan, S., Ting, J. G. W., Tan, J., Shekeran, S. G., Carling, D., ... & Cook, S. A. (2022). IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells. iScience, 25(9), 104806. PMC: PMC9386112 [5] ClinicalTrials.gov. (2025). Phase 1/1b/2 Study of Oral PMD-026 in Patients With Metastatic Breast Cancer. Identifier: NCT04115306. URL: https://clinicaltrials.gov/study/NCT04115306 [6] Spirrison, A. N., & Stipp, C. S. (2024). RSK1 and RSK2 as therapeutic targets: An up-to-date snapshot of emerging data. Expert Opinion on Therapeutic Targets, 28(12), 1167-1181. DOI: 10.1080/14728222.2024.2433123