1. Radical Longevity Requires Addressing Conceptual Gaps and Pursuing New Intervention Strategies

As a field, we do not yet agree on what aging is, do not know how molecular changes are coupled to functional deterioration, and do not understand mechanisms by which nature achieves radical longevity across cells or organisms (1, 2, 5, 72). The good news is that these gaps are now better addressable: measurement, learning approaches, perturbation tools, and human-scale data are improving rapidly. Another gap is a causal map: we do not know which components of the deleteriome are most limiting for function loss and survival. We also lack a systems-level understanding of how subsystem-specific aging trajectories interact to set whole-organism risk, and how interventions may be combined to amplify the effects and avoid trade-offs. Closing these gaps requires additional foundational work, causal perturbations at scale, longitudinal measurements, and integration across tissues and species. Some of the promising routes to radical longevity include: i) translating principles of embryonic rejuvenation to adult organisms, ii) cell-based strategies such as partial reprogramming and strengthening cell identity, iii) regeneration-driven rejuvenation, iv) replacement of cells, organs, or multiorgan systems, v) comparative biology-inspired engineering and complex intervention strategies, and vi) bioengineering that fuses or replaces biological tissues with materials, devices, closed-loop control systems, and computation. These approaches differ in evidentiary status and should be read as longer-term, partly speculative possibilities.