Stress responses and dynamic equilibrium: Key determinants of aging in the C. elegans clk-1 mutant

Systems biology is a helpful approach to study complex processes such as aging. Indeed, integrating experimental data with mathematical models and bioinformatics can help us to better understand the aging process.The long-lived mutants of C. elegans have generated extensive data about the molecular and cellular mechanisms involved in aging. Among these mutants, clk-1 is a well-studied gene that encodes for a ubiquitin precursor and exhibits a pleiotropic phenotype during aging, characterized by slow rate behaviors, high levels of mitochondrial ROS, autophagy induction, and metabolic changes. However, further elucidation is required to disentangle the relationship between these molecular changes and the phenotype (lifespan extension and changes in pharyngeal pumping, swimming, and defecation). We combined experimental data and modeling tools to represent the genetic interactions with a boolean network. We then inferred the differential equations for each node , following the boolean rules, to achieve a continuous approach. The results show that aak-2 (AMPK) is a critical gene for the long lifespan of clk-1, given its essential role in the induction of a stress response observed in the network attractors and the health condition and lifespan. To define the health condition of the strains (N2, clk-1, aak-2, and clk-1;aak-2), we propose a novel health index estimation based on the attrition of neuromuscular behaviors. We found that the attractor properties in the clk-1 mutant widely depend on a cyclic regulation for the stress response. From our findings, we infer that while stress responses can increase lifespan, health primarily relies on the amount of damage.