TFEB Lets Cells Live Long Enough to Become Senescent

This molecule is activated in emergencies.

by May 6, 2025

Introduction

The Transcription Factor EB (TFEB) plays a pivotal role in cellular responses to stress. Research has shown that TFEB activates during periods of cellular distress, a process intricately linked to the inactivation of the mechanistic target of rapamycin (mTOR). While this mechanism allows stressed cells to survive, it eventually leads to cellular senescence.

Inactivated by mTOR

Studies published in Aging Cell have elucidated the relationship between TFEB, mTOR, and cellular senescence. mTOR has been recognized as a key regulator of cellular growth and metabolism. When active, it phosphorylates TFEB, keeping it inactive within the cytoplasm. Conversely, conditions of nutrient scarcity or lysosomal stress prompt the inactivation of mTOR, leading to the activation of TFEB and a corresponding alteration in lysosomal function and autophagy [1].

Interestingly, even though mTOR contributes to the senescence-associated secretory phenotype (SASP), its inactivation during cellular stress events activates TFEB, which may explain how senescent cells continue to survive despite experiencing significant stress [2].

Surviving the Storm

In an experimental setup, researchers chemically induced senescence in human dermal fibroblasts, which are widely used in senescence research. Following a four-day treatment with a stress-inducing agent, the cells underwent considerable stress, leading to senescence approximately five days later. The results indicated:

• Lysosomal Activity: Elevated lysosomal activation during the stress phase, which diminished by the time senescence was fully established.
• Autophagic Flux: A decrease in the measurement of autophagosomes indicated impaired autophagic processes when lysosomes were stressed.
• Reversal of Stress Effects: Removal of stressors reinstated normal autophagic functions, even in senescent cells.

During the stress phase, TFEB was localized in the nucleus and was active, whereas, during actual senescence, TFEB was found in the cytosol in an inactive form, affirming the role of mTOR in modulating its function.

Interactions Between Signaling Pathways

Both AMPK (AMP-activated protein kinase) and Akt are indicators of oxidative stress that also regulate mTOR. The activation of AMPK increased during the stress phase but decreased in senescence. Conversely, Akt activity diminished during stress but heightened during senescence [4].

Consequence of TFEB Overexpression

Researchers further investigated the consequences of TFEB overexpression in cells. The findings showed:

While TFEB promotes survival to senescence, it does not directly influence the pathways leading to senescence itself. The implication of this finding is profound, indicating that targeting TFEB may potentially allow for selective elimination of stressed cells and reduce inflammatory responses associated with SASP.

Future Implications

Considering the role of TFEB in cellular senescence and survival, researchers propose:

• Investigating TFEB inhibitors as potential pre-senolytic agents to encourage the death of stressed cells before they can secrete pro-inflammatory signals.
• Exploring targeted methodologies to regulate TFEB's function, minimizing any side effects that could arise from broader interventions.

Conclusion

Understanding the interaction between TFEB, mTOR, and cellular senescence provides valuable insights into cellular maintenance and longevity. Future studies could facilitate the development of strategies that promote healthy aging and reduce the accumulation of dysfunctional senescent cells in tissues.

Literature Cited

[1] Napolitano, G., & Ballabio, A. (2016). TFEB at a glance. Journal of Cell Science, 129(13), 2475-2481.

[2] Carroll, B., et al. (2017). Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. Journal of Cell Biology, 216(7), 1949-1957.

[3] Curnock, R., et al. (2023). TFEB‐dependent lysosome biogenesis is required for senescence. The EMBO Journal, 42(9), e111241.

[4] Zhao, Y., et al. (2017). ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Molecular Cancer, 16, 1-12.