An AI-ready compositional framework for mechanistic aging research and in silico intervention testing

Abstract

Aging is a network-level phenomenon, with its hallmarks interacting through dense feedback loops across vastly different timescales. Decades of reductionist research have produced thousands of mechanistic models of narrow subsystems, but no straightforward way to integrate them into one comprehensive system. Consequently, whole-cell and multi-hallmark aging models remain rare, manually constructed, and relatively small, despite broad agreement on their importance. The emergence of autonomous research agents offers a way to distribute this modeling effort across humans and artificial intelligence and thereby greatly accelerate it, but only if the underlying substrate allows agents to readily compose and analyze models with built-in validation checks and modeling guidance, without extensive custom code. We present hallsim, a JAX-native compositional simulation framework designed as the mechanistic substrate for agent-orchestrated research. It provides composability, end-to-end differentiability, GPU execution, and automated analysis and model-selection tools that facilitate composite model construction and fine tuning. The framework makes it easier to propose a mechanistic hypothesis, integrate it into an existing composite, reparametrize it against observed data, and batch-test it across different initial conditions. We demonstrate the co-simulation and in silico perturbation of three independently published kinetic models spanning genomic instability, nutrient sensing, and proteostasis. The models are connected by four edges and calibrated against a public dataset. Additionally, we train a Neural ODE surrogate and compose it alongside the mechanistic modules in a hybrid composite, demonstrating that mechanistic and neural models can function as complementary components of the same system.