Inhibition of S6K Reduces Age-Related Inflammation and Extends Lifespan through the Endosomal-Lysosomal System

Research Background and Problem Description

As organisms age, chronic low-grade inflammation (inflammaging) and declined immune function (immunosenescence) become important pathological foundations of many diseases in the elderly, such as cancer, diabetes, and cardiovascular diseases. Research indicates that inhibiting the mechanistic target of rapamycin complex 1 (TORC1) can improve aging states in various organisms, significantly extending their lifespans. S6 kinase (S6K), a key effector molecule in the TORC1 signaling pathway, has mechanisms that have not been fully understood. This study, through experiments on fruit flies, demonstrates that the TORC1-S6K signaling pathway plays a crucial role in the accumulation of multilayer lysosomes and the regulation of the NF-κB-like immune deficiency (IMD) pathway, thereby impacting age-related inflammation and lifespan.

Research Source

This paper was authored by Pingze Zhang, James H. Catterson, Sebastian Grönke, and Linda Partridge, who are affiliated respectively with the Max Planck Institute for Biology of Ageing (Cologne, Germany), the Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (London, UK), and the Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh (Edinburgh, UK). The study was published in Nature Aging in April 2024.

Detailed Introduction to the Research Process

a) Detailed Stages and Steps of the Research Process

Using the fruit fly model, the study employed an inducible gene exchange system and an S6K RNAi line. The specific steps were as follows:

1. Experimental Design of Fruit Fly Model: 1.1 Using an inducible gene exchange system combined with S6K RNAi to inhibit the expression of specific genes in adult female flies. 1.2 Specifically downregulating S6K in tissues such as fat bodies, neurons, intestines, muscles, and heart tube to observe the impact on lifespan. The experimental results showed that only the inhibition of S6K in the fat body significantly extended lifespan.

2. Study on the Relationship Between Fat Bodies and Intestinal Health in Fruit Flies: 2.1 Using phosphorylated histone H3 (pH3) immunostaining to analyze the proliferation status of intestinal stem cells (ISCs), discovering that S6K activity in the fat body does not affect intestinal autophagy. 2.2 Utilizing Lysotracker staining and proteomics analysis to assess the impact of altered S6K activity in the fat body on the phosphorylation of glutamate-proline-tRNA synthetase (EPRS).

3. Proteomics Analysis of Fat Bodies: 3.1 Using TMT-labelled proteomics methods to analyze the impact of altered S6K activity on protein expression in the fat body, detecting 4101 proteins (S6K activation) and 4809 proteins (S6K inhibition). 3.2 Network expansion analysis revealed that proteins related to mitochondria, translation, and immunity were significantly upregulated in the elderly fat body, while the structure and function of intracellular macromolecules were weakened.

b) Main Results of the Research

1. Key Role of S6K Activity in Fat Body for Lifespan Extension: The experiments showed that rapamycin (Rapa) treatment could extend the lifespan of fruit flies by inhibiting the accumulation of multilayer lysosomes in the fat body. Enhancing S6K activity hinders this lifespan extension effect. Additionally, SYX13, a SNARE family protein responsible for endomembrane function, was identified as a downstream effector molecule of the TORC1-S6K signaling pathway.

2. Gender Differences in S6K and Inflammaging in the Fat Body: The study found that inflammaging was significantly higher in female flies than in males. Rapamycin treatment or S6K inhibition in male flies did not reduce their inflammation levels.

3. Regulation of TORC1 Signaling Pathway by the Endosomal-Lysosomal System: The research showed that TORC1 influences the structure and function of lysosomes in the fat body by regulating LYS13, thereby inhibiting age-related inflammation and extending lifespan.

c) Conclusion and Research Value

The study shows that inhibiting the TORC1-S6K signaling pathway can significantly reduce age-related inflammatory responses and extend the lifespan of fruit flies. This mechanism of regulating inflammation and immunosenescence via the endosomal-lysosomal system may also be applicable in mammals, holding significant scientific and practical value. The study also reveals the important role of the TORC1-S6K-SYX13 signaling axis in regulating inflammation, immune function, and lifespan, providing new insights for future research into delaying age-related diseases.

d) Research Highlights

1. Key Findings:

   • Inhibition of S6K in the fat body significantly extends lifespan and reduces inflammaging.
   • SYX13, as a downstream effector of the TORC1-S6K signaling pathway, plays a crucial role in regulating lysosomes in the fat body.
   • The TORC1-S6K-SYX13 signaling pathway specifically regulates inflammaging in one gender (female), thus affecting lifespan.

2. Novelty of the Research:

   • Using a fruit fly model to elucidate the role of the endosomal-lysosomal system in the TORC1 signaling pathway and its effects on aging inflammation and lifespan.
   • Proposing and verifying the critical role of SYX13 in regulating lysosome function, opening new directions for anti-aging research.

Summary

This article provides a detailed account of how the TORC1-S6K signaling pathway affects inflammaging and lifespan through the fruit fly model, identifying the key role of SYX13 in regulating lysosome structure and function and revealing physiological mechanisms underlying gender differences. The research offers significant references for mitigating inflammation and immune function decline during aging and has potential application prospects in aging studies of mammals.