A Grand Unified Experimental Framework for Delineating the Primary Etiology of Mammalian Aging: Actionable Protocols, Variable Trade-offs, and Novel Interventional Modalities

This preprint presents a comprehensive, actionable laboratory framework designed to definitively establish the primary hierarchical driver of mammalian aging. The field of geroscience is currently divided among competing paradigms: the Information Theory of Aging (ITOA) which emphasizes epigenetic drift following DNA double-strand break repair, metabolic and inflammaging hypotheses focusing on proteostasis (MANF and ACBP), and neurovascular hypotheses attributing systemic decline to cerebral autoregulatory failure. This document moves beyond correlative observations to provide strict, reductionist variable-trading protocols for academia and industry. It details experimental matrices to isolate Homologous Recombination (HR) from Alternative End Joining (Alt-EJ) to track sirtuin relocalization kinetics. Furthermore, it outlines the formulation and deployment of novel, highly differentiable gerotherapeutics, including Secreted Klotho (s-KL) mRNA lipid nanoparticles, circular RNA (circRNA) sponges targeting pro-aging microRNAs, and urokinase plasminogen activator receptor (uPAR)-targeted senolytic CAR-T cells. Finally, the framework integrates advanced artificial intelligence and machine learning pipelines to process the resulting multi-omic data, aiming to identify novel therapeutic targets and build uncertainty-aware epigenetic clocks. This blueprint provides the necessary methodology to decode the aging network and accelerate the commercialization of curative longevity interventions.