Reversing Cellular Aging: Our Approach to Longevity
Aging represents a gradual and progressive decline in an organism's ability to maintain cellular homeostasis. This deterioration stems from a reduced capacity of the cellular stress response to remediate both exogenous and endogenous stress challenges. We conducted our research with a focus on understanding dysfunction in the cellular stress response with the overall aim of regulating the stress response to achieve cellular homeostasis.
The cellular stress response is under control of second messenger signals that serve to translate cellular stress cues to the appropriate responses. In our research, we studied second messenger signaling, including oxidative signaling, for its ability to activate the cellular stress response across a broad range of stress cues. Intracellular reactive oxygen species (ROS) modify protein cysteines, thereby activating signal transduction pathways that regulate gene expression. In our work, we demonstrated that oxidative signaling regulates genes across seven different cytoprotective pathways (pro-survival, antioxidant, unfolded protein response, integrated stress response, NF-κB, and autophagic pathways). This cytoprotective program, through its expressed proteins, rejuvenates cells, thereby improving overall cellular health and increasing resilience to subsequent stress challenges.
Homeostatic oxidative signaling is necessary for the stress response to mediate its cytoprotective program. However, in aging, the loss of redox homeostasis disrupts the ability of the stress response to translate cellular stress cues to the appropriate responses. Specifically, supraphysiological levels of ROS impair transduction signaling, causing dysfunction in macromolecule complexes, which disrupt release of transcription factors, resulting in transcriptional dysfunction. This leaves cells with unresolved cellular stress, which drives aging.
AgeisBio has discovered an endogenous cellular mechanism to regulate oxidative signaling and to modulate its cytoprotective program for cellular rejuvenation. We discovered modulators of our target and studied the ability of our target modulators to reverse phenotypes seen in aging. We created aging phenotypes of chronic ER, inflammatory and oxidative stress and demonstrated that our target modulators reduced ER, inflammatory and oxidative stresses depending on their ability to achieve redox homeostasis. We studied the effects of our target modulators in senescence. We created phenotypes of oxidative stress-induced senescence and demonstrated the ability of our target modulators to reverse oxidative stress-induced senescence. We also senesced cells using both oxidative and replicative stress and found that our target modulators induced a senolytic response in senescent cells with enhanced oxidation and DNA damage levels. We also assessed the ability of our target modulators to rescue cells from ROS-induced apoptosis, even when the challenge was significant. In addition, we demonstrated the ability of our target modulators to rescue cells from cell death induced by Ca2+ overload.
References:
1. Dutta, N., Garcia, G., and Higuchi-Sanabria, R. (2022). Hijacking Cellular Stress Responses to
Promote Lifespan. Frontiers in Aging 3, 860404. 10.3389/fragi.2022.860404.
2. Hartl, F. U. (2016). Cellular Homeostasis and Aging. Annual Review of Biochemistry 85, 1–4. 10.1146/annurev-biochem-011116-110806.
3. Kourtis, N., and Tavernarakis, N. (2011). Cellular stress response pathways and ageing: intricate molecular relationships. The EMBO Journal 30, 2520–2531. 10.1038/emboj.2011.162.
4. Liu, D., Ma, D., Wang, T., and Zheng, C. (2024). Oxidative Stress: Signaling Pathways, Biological Functions, and Disease. Antioxidants (Basel) 13, 682. 10.3390/antiox13060682.
5. Schieber, M., and Chandel, N. S. (2014). ROS Function in Redox Signaling and Oxidative Stress. Current Biology 24, R453–R462. 10.1016/j.cub.2014.03.034.